ORCID Profile
0000-0002-0020-6637
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
University of Melbourne
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Immunology not elsewhere classified | Haematology | Other Biological Sciences | Biological Sciences not elsewhere classified
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Wiley
Date: 15-04-1998
Publisher: Wiley
Date: 09-08-2011
DOI: 10.1038/ICB.2011.48
Publisher: Wiley
Date: 06-01-2011
DOI: 10.1002/JNR.22533
Abstract: Microglia play important roles in the damaged or degenerating adult nervous system. However, the role of microglia in embryonic brain development is still largely uncharacterized. Here we show that microglia are present in regions of the developing brain that contain neural precursors from E11 onward. To determine whether these microglia are important for neural precursor maintenance or self-renewal, we cultured embryonic neural precursors from the cortex of PU.1(-/-) mice, which we show lack resident microglia during embryogenesis. Cell survival and neurogenesis were similar in cultures from PU.1(-/-) vs. PU.1(+/+) mice, but precursor proliferation and astrogenesis were both reduced. Cortical precursors depleted of microglia also displayed decreased precursor proliferation and astrogenesis, and these deficits could be rescued when microglia were added back to the cultures. Moreover, when the number of microglia present in cortical precursor cultures was increased above normal levels, astrogenesis but not neurogenesis was increased. Together these results demonstrate that microglia present within the embryonic neural precursor niche can regulate neural precursor development and suggest that alterations in microglial number as a consequence of genetic or pathological events could perturb neural development by directly affecting embryonic neural precursors.
Publisher: Wiley
Date: 25-06-2011
DOI: 10.1016/J.FEBSLET.2011.06.022
Abstract: B lymphocyte induced maturation protein-1 (Blimp-1) is a transcription repressor of the Krueppel-like family. Blimp-1 plays important roles in developmental processes, such as of germ cells and hair follicle stem cells. In B lymphocytes Blimp-1 orchestrates the terminal differentiation into plasma cells. We discovered that Blimp-1 undergoes SUMOylation by SUMO-1. This SUMOylation is modulated by the SUMO protease SENP1. While Blimp-1 is relatively stable in 293T cells, a fusion with SUMO1 rendered it to rapid proteasomal degradation. Increase in SENP1 activity stabilized Blimp-1, while a decrease promoted its degradation. Our data indicate that SUMOylation of Blimp-1 regulates its intracellular stability.
Publisher: Elsevier BV
Date: 02-2013
Abstract: Regulatory T (Treg) cells are essential for immunological tolerance and homeostasis. Although forkhead box (Fox)p3 is continually required to reinforce the Treg cell program, Treg cells can also undergo stimulus-specific differentiation that is regulated by transcription factors typically associated with the differentiation of conventional CD4(+) T cells. This results in effector Treg (eTreg) cells with unique migratory and functional properties matched to the stimulus that elicited the initial response. Despite this functional and transcriptional heterogeneity, expression of the transcription factor B lymphocyte-induced maturation protein (Blimp)-1, a key player in late B cell and conventional T cell differentiation, is common to all eTreg cells. Here, we discuss the factors that control the differentiation of eTreg cells and their importance in disease settings.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2015
DOI: 10.1038/NRI3795
Abstract: The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.
Publisher: Elsevier BV
Date: 04-1998
Abstract: Pax-5 codes for the transcription factor BSAP which is expressed throughout B cell development except in terminally differentiated plasma cells. Gene targeting experiments in the mouse revealed a differential dependency of fetal and adult B-lymphopoiesis on this transcription factor. BSAP is required for B-lineage commitment in the fetal liver and for progression beyond an early pro-B cell stage in adult bone marrow. The characterization of Pax-5-deficient pro-B cells demonstrated an important role of BSAP in the regulation of the CD19, mb-1 (Ig alpha) and N-myc genes as well as in the developmental pathway controlling VH-to-DHJH recombination at the immunoglobulin heavy-chain (IgH) locus. The human PAX-5 gene was recently shown to participate together with the IgH locus in the chromosomal translocation t(9 )(p13 q32). This translocation is characteristic of a small subset of non-Hodgkin lymphomas exhibiting plasmacytoid differentiation. The translocated PAX-5 gene is deregulated by the insertion of IgH regulatory elements into its 5' region, which may contribute to tumorigenesis by interfering with the shut-down of PAX-5 transcription and thus with the completion of plasma cell differentiation.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JAUT.2018.04.003
Abstract: Regulatory T (T
Publisher: Rockefeller University Press
Date: 08-10-2007
DOI: 10.1084/JEM.20071351
Abstract: Interferon-producing killer dendritic cells (IKDCs) have been described as possessing the lytic potential of NK cells and the antigen-presenting capacity of dendritic cells (DCs). In this study, we examine the lytic function and antigen-presenting capacity of mouse spleen IKDCs, including those found in DC preparations. IKDCs efficiently killed NK cell targets, without requiring additional activation stimuli. However, in our hands, when exposed to protein antigen or to MHC class II peptide, IKDCs induced little or no T cell proliferation relative to conventional DCs or plasmacytoid DCs, either before or after activation with CpG, or in several disease models. Certain developmental features indicated that IKDCs resembled NK cells more than DCs. IKDCs, like NK cells, did not express the transcription factor PU.1 and were absent from recombinase activating gene-2–null, common γ-chain–null (Rag2−/−Il2rg−/−) mice. When cultured with IL-15 and -18, IKDCs proliferated extensively, like NK cells. Under these conditions, a proportion of expanded IKDCs and NK cells expressed high levels of surface MHC class II. However, even such MHC class II+ IKDCs and NK cells induced poor T cell proliferative responses compared with DCs. Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells.
Publisher: The American Association of Immunologists
Date: 05-2013
Abstract: The transcription factor inhibitor of DNA binding (Id)2 modulates T cell fate decisions, but the molecular mechanism underpinning this regulation is unclear. In this study we show that loss of Id2 cripples effector differentiation and instead programs CD8+ T cells to adopt a memory fate with increased Eomesodermin and Tcf7 expression. We demonstrate that Id2 restrains CD8+ T cell memory differentiation by inhibiting E2A-mediated direct activation of Tcf7 and that Id2 expression level mirrors T cell memory recall capacity. As a result of the defective effector differentiation, Id2-deficient CD8+ T cells fail to induce sufficient Tbx21 expression to generate short-lived effector CD8+ T cells. Our findings reveal that the Id2/E2A axis orchestrates T cell differentiation through the induction or repression of downstream transcription factors essential for effector and memory T cell differentiation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1994
DOI: 10.1097/00001756-199412000-00055
Abstract: RNA editing has been shown to be critical in generating the molecular ersity of rodent kainate receptors. We have examined cDNAs derived from various human brain sources to assess the occurrence and extent of RNA editing in human brain. Comparison of genomic and cDNA sequences revealed extensive editing of the human EAA4 (GluR6) mRNA at the isoleucine/valine, tyrosine/cysteine sites of the transmembrane I region, and the glutamine/arginine site of the transmembrane II region. Of the eight potential molecular variants generated by the nucleotide exchange, five were observed in the tissues examined. The distribution of the various RNA editing combinations were not uniform, and displayed tissue and/or age dependent distribution. Editing of the glutamine/arginine site was also confirmed for EAA3 (GluR5), which displays a significantly higher extent of editing in specific human brain regions compared with rodent whole brain. Hence, it can be concluded that RNA editing is a determinant of the phenotype of human kainate receptor complexes.
Publisher: Informa UK Limited
Date: 18-10-2006
DOI: 10.4161/CC.5.21.3396
Abstract: The transcription factor Pax5 is required for many aspects of B-lymphopoiesis including lineage commitment, immunoglobulin rearrangement, pre-BCR signalling and mature B cell survival. Pax5 regulates B cell lineage commitment by concurrently activating cell specific gene expression as well as suppressing the expression of genes associated with non-B cell fates. The identity of the molecular targets of Pax5-mediated gene repression is the subject of much current interest. Recent studies have documented the essential nature of the Pax5 mediated repression of the stem cell transcriptional program, as well as the silencing of lineage inappropriate gene expression, for B cell development. Surprisingly the repression of genes by Pax5 continues throughout lymphopoiesis, with the loss of Pax5 in mature B cell resulting in the reactivation of the same Pax5 targets during plasma cell differentiation. These recent insights into the mechanism of action of Pax5 in controlling B cell identity will be discussed.
Publisher: Cold Spring Harbor Laboratory
Date: 15-02-1997
DOI: 10.1101/GAD.11.4.476
Abstract: The Pax5 gene coding for the transcription factor BSAP has an essential role in B lymphopoiesis and midbrain development. Here we present a detailed analysis of the B-cell phenotype of Pax5 mutant mice that revealed a differential dependency of fetal and adult B lymphopoiesis on this transcriptional regulator. B-cell development is arrested in the bone marrow at the early pro-B (pre-BI) cell stage, which is characterized by expression of the early markers c-kit, CD43, lambda5, VpreB, and HSA and the absence of the later markers CD25 and BP-1. These pre-BI cells fail to express the BSAP target gene CD19 and are capable of long-term proliferation in vitro in the presence of stromal cells and IL-7. B-lymphoid progenitors could not be detected in the fetal liver of Pax5 mutant embryos. However, Pax5-deficient fetal liver cells gave rise to the development of pre-BI cells in bone marrow on transplantation into lethally irradiated mice. These data indicate different functions of Pax5 in the distinctive microenvironments of fetal liver and adult bone marrow. As shown by PCR analyses, the pre-BI cells in Pax5-deficient bone marrow have undergone D(H)-to-J(H) rearrangement of the immunoglobulin heavy-chain locus at normal frequency. In contrast, V(H)-to-D(H)J(H) rearrangements were reduced approximately 50-fold in Pax5-deficient pre-BI cells, suggesting a role for Pax5 in the developmental pathway controlling V-to-DJ recombination.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
Publisher: Rockefeller University Press
Date: 06-10-2014
DOI: 10.1084/JEM.20140338
Abstract: A single microRNA (miRNA) can regulate the expression of many genes, though the level of repression imparted on any given target is generally low. How then is the selective pressure for a single miRNA/target interaction maintained across long evolutionary distances? We addressed this problem by disrupting in vivo the interaction between miR-155 and PU.1 in mice. Remarkably, this interaction proved to be key to promoting optimal T cell–dependent B cell responses, a previously unrecognized role for PU.1. Mechanistically, miR-155 inhibits PU.1 expression, leading to Pax5 down-regulation and the initiation of the plasma cell differentiation pathway. Additional PU.1 targets include a network of genes whose products are involved in adhesion, with direct links to B–T cell interactions. We conclude that the evolutionary adaptive selection of the miR-155–PU.1 interaction is exercised through the effectiveness of terminal B cell differentiation.
Publisher: The American Association of Immunologists
Date: 15-10-2009
Abstract: The Ets transcription factor PU.1 is a master regulator for the development of multiple lineages during hematopoiesis. The expression pattern of PU.1 is dynamically regulated during early T lineage development in the thymus. We previously revealed that PU.1 delineates heterogeneity of effector Th2 populations. In this study, we further define the function of PU.1 on the Th2 phenotype using mice that specifically lack PU.1 in T cells using an lck-Cre transgene with a conditional Sfpi1 allele (Sfpi1lck−/−). Although deletion of PU.1 by the lck-Cre transgene does not affect T cell development, Sfpi1lck−/− T cells have a lower activation threshold than wild-type T cells. When TCR engagement is limiting, Sfpi1lck−/− T cells cultured in Th2 polarizing conditions secrete higher levels of Th2 cytokines and have greater cytokine homogeneity than wild-type cells. We show that PU.1 modulates the levels of TCR expression in CD4+ T cells by regulating the DNA-binding activity of GATA-3 and limiting GATA-3 regulation of TCR gene expression. GATA-3-dependent regulation of TCR expression is also observed in Th1 and Th2 cells. In CD4+ T cells, PU.1 expression segregates into subpopulations of cells that have lower levels of surface TCR, suggesting that PU.1 contributes to the heterogeneity of TCR expression. Thus, we have identified a mechanism whereby increased GATA-3 function in the absence of the antagonizing activity of PU.1 leads to increased TCR expression, a reduced activation threshold, and increased homogeneity in Th2 populations.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.CELREP.2016.08.056
Abstract: How functionally erse populations of pathogen-specific killer T cells are generated during an immune response remains unclear. Here, we propose that fine-tuning of CD8αβ co-receptor levels via histone acetylation plays a role in lineage fate. We show that lysine acetyltransferase 6A (KAT6A) is responsible for maintaining permissive Cd8 gene transcription and enabling robust effector responses during infection. KAT6A-deficient CD8(+) T cells downregulated surface CD8 co-receptor expression during clonal expansion, a finding linked to reduced Cd8α transcripts and histone-H3 lysine 9 acetylation of the Cd8 locus. Loss of CD8 expression in KAT6A-deficient T cells correlated with reduced TCR signaling intensity and accelerated contraction of the effector-like memory compartment, whereas the long-lived memory compartment appeared unaffected, a result phenocopied by the removal of the Cd8 E8I enhancer element. These findings suggest a direct role of CD8αβ co-receptor expression and histone acetylation in shaping functional ersity within the cytotoxic T cell pool.
Publisher: American Society of Hematology
Date: 19-05-2011
DOI: 10.1182/BLOOD-2010-11-318956
Abstract: Natural killer (NK) cells are generated in the bone marrow (BM) from lymphoid progenitors. Although several different maturation states of committed NK cells have been described, the initial stages of NK-cell differentiation from the common lymphoid progenitor are not well understood. Here we describe the identification of the earliest committed NK-cell precursors in the BM. These precursors, termed pre-pro NK cells, lack the expression of most canonical NK cell–specific surface markers but express the transcription factor inhibitor of DNA binding 2 and high levels of the IL-7 receptor. In vitro differentiation studies demonstrate that pre-pro NK cells are committed to NK-cell lineage and appear to be upstream of the previously identified NK-cell progenitor population.
Publisher: Rockefeller University Press
Date: 08-02-2010
DOI: 10.1084/JEM.20091777
Abstract: Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2023
Publisher: Research Square Platform LLC
Date: 11-09-2023
Publisher: Springer Science and Business Media LLC
Date: 03-03-2013
DOI: 10.1038/NI.2545
Publisher: Springer Science and Business Media LLC
Date: 26-02-2020
Publisher: The American Association of Immunologists
Date: 2019
Abstract: The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell–dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138+Blimp1+ splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.
Publisher: Wiley
Date: 25-10-2010
Publisher: American Society of Hematology
Date: 15-11-2018
DOI: 10.1182/BLOOD-2018-05-850727
Abstract: Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis,” as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2009
DOI: 10.1038/NI.1694
Abstract: Despite advances in the identification of lymphoid-restricted progenitor cells, the transcription factors essential for their generation remain to be identified. Here we describe an unexpected function for the myeloid oncogene product Mef2c in lymphoid development. Mef2c deficiency was associated with profound defects in the production of B cells, T cells, natural killer cells and common lymphoid progenitor cells and an enhanced myeloid output. In multipotent progenitors, Mef2c was required for the proper expression of several key lymphoid regulators and restriction of the myeloid fate. Our studies also show that Mef2c was a critical transcriptional target of the transcription factor PU.1 during lymphopoiesis. Thus, Mef2c is a crucial component of the transcriptional network that regulates cell fate 'choice' in multipotent progenitors.
Publisher: Elsevier BV
Date: 10-2020
Publisher: American Society of Hematology
Date: 10-10-2013
DOI: 10.1182/BLOOD-2013-02-484055
Abstract: PRC1 and PRC2 have opposing activity in Eμ-myc lymphoma. Inhibition of PRC2 leads to increased self-renewal in B-cell progenitors.
Publisher: Springer Science and Business Media LLC
Date: 10-04-2013
DOI: 10.1038/NATURE12026
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-12-2007
Abstract: A critical issue for cancer biology and therapy is whether most tumor cells or only rare “cancer stem cells” sustain tumor growth. Although the latter model seems supported by the minute proportion of human leukemia cells that can grow in immunodeficient mice, evidence that more than 10% of cells in many mouse leukemias and lymphomas are transplantable challenges its generality.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.COI.2019.04.007
Abstract: The differentiation of B cells into antibody-secreting plasma cells is associated with profound changes in morphology, lifespan, and cellular metabolism that are needed to support high rates of antibody production. These processes are driven by dramatic alterations to the transcriptional program and to the organization of the nucleus itself that in turn are regulated by the activity of a select group of transcription factors and epigenetic regulators. Although the core differentiation program is conserved in all mature B cells, subset-specific regulators, such as those found in B1 or memory B cells, provide additional complexity. Here, we review the key components of the gene regulatory network controlling B-cell terminal differentiation, with an emphasis on the new players and processes that have emerged in recent years.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-07-2007
Abstract: The cancer stem cell hypothesis postulates that tumor growth is driven by a rare subpopulation of tumor cells. Much of the supporting evidence for this intriguing idea is derived from xenotransplantation experiments in which human leukemia cells are grown in immunocompromised mice. We show that, when lymphomas and leukemias of mouse origin are transplanted into histocompatible mice, a very high frequency (at least 1 in 10) of the tumor cells can seed tumor growth. We suggest that the low frequency of tumor-sustaining cells observed in xenotransplantation studies may reflect the limited ability of human tumor cells to adapt to growth in a foreign (mouse) milieu.
Publisher: Elsevier BV
Date: 12-2020
DOI: 10.1016/J.CELL.2020.10.048
Abstract: Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1994
Publisher: Rockefeller University Press
Date: 02-05-2005
DOI: 10.1084/JEM.20042325
Abstract: Resting B cells can be cultured to induce antibody-secreting cell (ASC) differentiation in vitro. A quantitative analysis of cell behavior during such a culture allows the influences of different stimuli and gene products to be measured. The application of this analytical system revealed that the OBF-1 transcriptional coactivator, whose loss impairs antibody production in vivo, has two effects on ASC development. Although OBF-1 represses early T cell–dependent (TD) differentiation, it is also critical for the completion of the final stages of ASC development. Under these conditions, the loss of OBF-1 blocks the genetic program of ASC differentiation so that Blimp-1 rdm1 induction fails, and bcl-6, Pax5, and AID are not repressed as in control ASC. Retroviral complementation confirmed that OBF-1 was the critical entity. Surprisingly, when cells were cultured in lipopolysaccharide to mimic T cell–independent conditions, OBF-1–null B cells differentiated normally to ASC. In the OBF-1−/− ASC generated under either culture regimen, antibody production was normal or only modestly reduced, revealing that Ig genes are not directly dependent on OBF-1 for their expression. The differential requirement for OBF-1 in TD ASC generation was confirmed in vivo. These studies define a new regulatory role for OBF-1 in determining the cell-autonomous capacity of B cells to undergo terminal differentiation in response to different immunological signals.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Wiley
Date: 2001
DOI: 10.1002/GENE.1042
Abstract: Morpholino (MO) based inhibition of translational initiation represents an attractive methodology to eliminate gene function during Xenopus development (Heasman et al., 2000). However, the degree to which a given target protein can be eliminated and the longevity of this effect during embryogenesis has not been documented. To examine the efficacy of MOs, we have used transgenic Xenopus lines that harbour known numbers of integrations of a GFP reporter under the control of the ubiquitous and highly expressed CMV promoter (Fig. 1a). In addition we have investigated the longevity of the inhibitory effect by using transgenic lines expressing GFP specifically in the lens of tadpoles. These transgenic lines represent the ideal control for the technique as the promoters are highly expressed and GFP can be easily detected by fluorescence and immunoblotting. Moreover, as GFP has no function in development, the levels of inhibition can be tested in an otherwise normal in idual. Here we report that MOs are able to efficiently and specifically inhibit the translation of GFP in transgenic lines from Xenopus laevis and Xenopus tropicalis and the inhibitory effect is long-lived, lasting into the tadpole stages. genesis 30:110--113, 2001.
Publisher: Cold Spring Harbor Laboratory
Date: 03-12-2019
DOI: 10.1101/861542
Abstract: B-cell development is initiated by the stepwise differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating the mature B-cells that mediate protective immunity. This highly regulated process also generates clonal immunological ersity via recombination of immunoglobulin genes. While several transcription factors that control B-cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene ( Erg ) is essential for the earliest steps in B-cell differentiation. Erg initiates a transcriptional network involving the B-cell lineage defining genes, Ebf1 and Pax5 , that directly promotes the expression of key genes involved in V(D)J recombination and formation of the B-cell receptor. Complementation of the Erg-deficiency with a productively rearranged immunoglobulin gene rescued B-cell development, demonstrating that Erg is an essential and exquisitely stage specific regulator of the gene regulatory network controlling B-lymphopoiesis.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-06-2022
Abstract: Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically “cold” tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti–programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8 + T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.IMMUNI.2015.12.007
Abstract: The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2013
DOI: 10.1038/NI.2527
Publisher: Springer Science and Business Media LLC
Date: 19-10-2020
DOI: 10.1038/S41590-020-0799-X
Abstract: A classical view of blood cell development is that multipotent hematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. Lin
Publisher: Elsevier
Date: 2008
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer New York
Date: 2011
DOI: 10.1007/978-1-4419-5632-3_8
Abstract: B lymphocyte maturation-induced protein-1 (Blimp1) is a transcriptional repressor expressed in erse cell types. In the adaptive immune system, Blimp1 is expressed in lymphocytes that have undergone effector differentiation. Blimp1 is a master regulator of plasma cell differentiation and plays important roles in controlling T cell homeostasis and effector differentiation. Blimp1 can be induced by a variety of cytokines including IL-2, IL-4, IL-12, and IL-21 in addition to TCR and co-stimulatory signals. Blimp1-deficient mice develop spontaneous inflammatory disease mediated by infiltration of activated T cells into tissues. During immune responses Blimp1 is required for the differentiation of plasma cells as well as short-lived CD8(+) cytotoxic T cells. Mounting evidence suggests that Blimp1 plays a common role in the terminal differentiation of multiple cell subsets.
Publisher: MDPI AG
Date: 24-07-2018
DOI: 10.3390/IJMS19082161
Abstract: Antibody Secreting Cells (ASCs) are a fundamental component of humoral immunity, however, deregulated or excessive antibody production contributes to the pathology of autoimmune diseases, while transformation of ASCs results in the malignancy Multiple Myeloma (MM). Despite substantial recent improvements in treating these conditions, there is as yet no widely used ASC-specific therapeutic approach, highlighting a critical need to identify novel methods of targeting normal and malignant ASCs. Surface molecules specifically expressed by the target cell population represent ideal candidates for a monoclonal antibody-based therapy. By interrogating the ASC gene signature that we previously defined we identified three surface proteins, Plpp5, Clptm1l and Itm2c, which represent potential targets for novel MM treatments. Plpp5, Clptm1l and Itm2c are highly and selectively expressed by mouse and human ASCs as well as MM cells. To investigate the function of these proteins within the humoral immune system we have generated three novel mouse strains, each carrying a loss-of-function mutation in either Plpp5, Clptm1l or Itm2c. Through analysis of these novel strains, we have shown that Plpp5, Clptm1l and Itm2c are dispensable for the development, maturation and differentiation of B-lymphocytes, and for the production of antibodies by ASCs. As adult mice lacking either protein showed no apparent disease phenotypes, it is likely that targeting these molecules on ASCs will have minimal on-target adverse effects.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
Publisher: Wiley
Date: 07-11-2006
Publisher: Elsevier BV
Date: 12-1997
DOI: 10.1016/S0171-2985(97)80043-5
Abstract: Knowledge about HPV infection in the oral cavity/oropharynx may contribute to the elucidation of the role it plays in Head and Neck Squamous Cell Carcinoma (HNSCC). To determine the effectiveness of the methodology used for s ling the oral cavity and oropharynx mucosae and to determine the prevalence of HPV in the oral cavity and oropharynx of adults and children. The study population was served by an assistance program in a rural district of São Paulo. The subjects were asked to donate s les regardless of complaints. The study included 47 men, 77 women and 22 children, of which the oral cavity s les were obtained by gargling with commercially-available antiseptic mouthwash. We found 3 positive s les (2.4%) in adults: 2 HPV 55 and one HPV 58. No positive results were found in children. Furthermore we concluded that the s ling method with the mouthwash proved effective and fast for the detection of HPV in the oral cavity and oropharynx in the general population.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.IMMUNI.2018.05.007
Abstract: The mechanistic understanding of gene-expression regulation is still evolving. In this issue of Immunity, Hosokawa et al. (2018) reveal that PU.1 represses transcription indirectly during early T cell development by "stealing" other regulators such as Runx1 and Satb1 from their DNA binding sites.
Publisher: Rockefeller University Press
Date: 23-05-2016
DOI: 10.1084/JEM.20152003
Abstract: The generation of high-affinity antibodies requires germinal center (GC) development and differentiation of long-lived plasma cells in a multilayered process that is tightly controlled by the activity of multiple transcription factors. Here, we reveal a new layer of complexity by demonstrating that dynamic changes in Id3 and E-protein activity govern both GC and plasma cell differentiation. We show that down-regulation of Id3 in B cells is essential for releasing E2A and E2-2, which in a redundant manner are required for antigen-induced B cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors, including Blimp1, Xbp1, and CXCR4, and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation.
Publisher: eLife Sciences Publications, Ltd
Date: 10-11-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2006
Abstract: Genetically primed adult C57BL mice were deleted of exon 5 of the gene encoding the transcription factor PU.1 by IFN activation of Cre recombinase. After a 13-week delay, conditionally deleted ( PU.1 -/- ) mice began dying of myeloid leukemia, and 95% of the mice surviving from early postinduction death developed transplantable myeloid leukemia whose cells were deleted of PU.1 and uniformly Gr-1 positive. The leukemic cells formed autonomous colonies in semisolid culture with varying clonal efficiency, but colony formation was enhanced by IL-3 and sometimes by granulocyte-macrophage colony-stimulating factor. Nine of 13 tumors analyzed had developed a capacity for autocrine IL-3 or granulocyte-macrophage colony-stimulating factor production, and there was evidence of rearrangement of the IL-3 gene. Acquisition of autocrine growth-factor production and autonomous growth appeared to be major events in the transformation of conditionally deleted PU.1 -/- cells to fully developed myeloid leukemic populations.
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2020
DOI: 10.1101/2020.05.28.120188
Abstract: Extrinsic regulation of single haematopoietic stem and progenitor cell (HSPC) fate is crucial for immune cell development. Here, we examine the aetiology of Flt3 ligand (Flt3L)-mediated emergency development of type 1 conventional dendritic cells (cDC1s), which results in enhanced immunity against infections and cancer. Using cellular barcoding, we demonstrate a predominant role of enhanced clonal expansion and moderate contribution via recruitment of additional cDC1-generating HSPCs. The selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising output to other lineages. To understand the molecular hallmarks early during a Flt3L response, we develop Divi-Seq to simultaneously profile cell ision history, surface phenotype and transcriptional state of single HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative ‘early progenitor’-like state, which leads to selective emergence of CD11c + cKit + transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy at a clonal level.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2014
DOI: 10.1038/NM.3442
Abstract: Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy in iduals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.
Publisher: The American Association of Immunologists
Date: 08-2009
Abstract: Th2 cells can be sub ided into subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)4. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. Infection of total Th2 cells, and IL-10 nonsecreting cells, with retrovirus-expressing IRF4, resulted in increased IL-4 and IL-10 expression, no change in IL-5 or IL-13 production and decreased Il9 transcription. Transfection of an IRF4-specific small interfering RNA into Th2 cells decreases IL-10 production. IRF4 directly binds the Il10 gene as evidenced by chromatin immunoprecipitation assay, and regulates Il10 control elements in a reporter assay. IRF4 interacts with PU.1, and in PU.1-deficient T cells there was an increase in IRF4 binding to the Il10 gene, and in the ability of IRF4 to induce IL-10 production compared with wild-type cells and Il10 promoter activity in a reporter assay. Further heterogeneity of IRF4 expression was observed in Th2 cells analyzed for expression of multiple Th2 cytokines. Thus, IRF4 promotes the expression of a subset of Th2 cytokines and contributes to Th2 heterogeneity.
Publisher: Wiley
Date: 05-02-2020
DOI: 10.1111/IMCB.12313
Abstract: The NZB/W F1 (F1) mice develop severe disease that is similar to human systemic lupus erythematosus. By contrast, each parent strain, NZB or NZW, has limited autoimmunity, suggesting traits of both strains contribute to pathogenesis. Although many of the contributing genes have been identified, the contributing cellular abnormality associated with each parent strain remains unresolved. Given that plasmacytoid dendritic cells (pDCs) are key to the pathogenesis of lupus, we investigated the properties of pDCs from NZB and NZW mice. We found that NZB mouse had higher numbers of pDCs, with much of the increase being contributed by a more abundant CD8
Publisher: Wiley
Date: 23-10-2006
DOI: 10.1111/J.1399-3089.2006.00348.X
Abstract: Natural killer (NK) cells have emerged as major players in anti-viral and anti-tumour immune responses. Like cytotoxic T lymphocytes (CTL), they express perforin and are potent secretors of gamma-interferon (IFN-gamma). However, there is conflicting evidence about their role in mediating rejection of xenogeneic tissue. A pig-to-mouse peritoneal cell model of xenotransplantation was used to investigate the effect of NK deficiency on xenograft recovery and the possible mechanisms behind this NK-mediated graft rejection. gamma c(-/-)RAG(-/-) mice were used as a model of NK deficiency. Additionally, NK cells were depleted in RAG(-/-) mice using anti-asialo GM1. The contributions of IFN-gamma, perforin and NKT cells were studied using knock-out mice that were depleted in vivo of T cells. Mice were injected with 10(7) pig cells intraperitoneally and peritoneal fluid was assessed 5 days later for xenograft recovery and phenotypic analysis. The requirement for NK cells for xenograft rejection was also assessed using luciferase-transfected porcine cells in a renal subcapsular model of transplantation. Pig cell recovery was enhanced in both gamma c(-/-)RAG(-/-) and NK-depleted RAG(-/-) mice when compared with RAG(-/-) control mice. IFN-gamma(-/-) mice depleted of T cells also demonstrated superior graft survival compared with their B6 counterparts. However, there were minimal graft survival differences between Pfp(-/-) and B6 control mice. Similarly, a deficiency in NKT cells did not improve pig xenograft recovery from the peritoneum of these mice. Therefore, we conclude that NK cells, but not NKT cells, are important mediators of xenograft rejection in the peritoneal cavity, and that their role may be unmasked in the absence of T cells. The mechanism for this xenorejection appears to involve IFN-gamma but is perforin independent.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2017
DOI: 10.1038/NCOMMS15632
Abstract: Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.
Publisher: American Society of Hematology
Date: 15-11-2007
DOI: 10.1182/BLOOD-2006-10-053124
Abstract: The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix transcription factor expressed in erythroid, megakaryocyte, and mast-cell lineages. SCL is essential for growth of megakaryocyte and erythroid progenitors. We have used a conditional knockout of SCL (SCL−/Δ) to examine its function in mast cells, critical effectors of the immune system. SCL−/Δ mice had markedly increased numbers of mast-cell progenitors (MCPs) within the peritoneal fluid, bone marrow, and spleen. Fractionation of bone marrow myeloid progenitors demonstrated that these MCPs were present in the megakaryocyte-erythroid–restricted cell fraction. In contrast, unilineage MCPs from control mice were present in the cell fraction with granulocyte-macrophage potential. The aberrant mast-cell differentiation of SCL−/Δ megakaryocyte-erythroid progenitors was associated with increased expression of GATA-2. Despite increased numbers of MCPs in SCL−/Δ mice, numbers of mature tissue mast cells were not increased unless SCL−/Δ mice were treated with IL-3 and stem-cell factor. In part, this may be due to a requirement for SCL in normal mast-cell maturation: SCL−/Δ mast cells had reduced expression of the high-affinity IgE receptor and mast cell proteases, MCP-5 and MCP-6. Together, these studies suggest that loss of SCL leads to aberrant mast-cell differentiation of megakaryocyte-erythroid progenitors.
Publisher: Wiley
Date: 03-1995
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.SMIM.2011.08.010
Abstract: Upon activation by antigen, mature B cells undergo immunoglobulin class switch recombination and differentiate into antibody-secreting plasma cells, the endpoint of the B cell developmental lineage. Careful quantitation of these processes, which are stochastic, independent and strongly linked to the ision history of the cell, has revealed that populations of B cells behave in a highly predictable manner. Considerable progress has also been made in the last few years in understanding the gene regulatory network that controls the B cell to plasma cell transition. The mutually exclusive transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors, those that maintain the B cell program, including Pax5, Bach2 and Bcl6, and those that promote and facilitate plasma cell differentiation, notably Irf4, Blimp1 and Xbp1. In this review, we discuss progress in the definition of both the transcriptional and cellular events occurring during late B cell differentiation, as integrating these two approaches is crucial to defining a regulatory network that faithfully reflects the stochastic features and complexity of the humoral immune response.
Publisher: Rockefeller University Press
Date: 15-06-2015
DOI: 10.1084/JEM.20150191
Abstract: Plasma cell migration is crucial to immunity, but little is known about the molecular regulators of their migratory programs. Here, we detail the critical role of the transcription factor c-Myb in determining plasma cell location. In the absence of c-Myb, no IgG+ antigen-specific plasma cells were detected in the bone marrow after immunization or virus infection. This was correlated with a dramatic reduction of plasma cells in peripheral blood, mislocalization in spleen, and an inability of c-Myb–deficient plasma cells to migrate along a CXCL12 gradient. Therefore, c-Myb plays an essential, novel role in establishing the long-lived plasma cell population in the BM via responsiveness to chemokine migration cues.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.IMMUNI.2010.05.005
Abstract: The transcription factor PU.1 plays multiple context and concentration dependent roles in lymphoid and myeloid cell development. Here we showed that PU.1 (encoded by Sfpi1) was essential for dendritic cell (DC) development in vivo and that conditional ablation of PU.1 in defined precursors, including the common DC progenitor, blocked Flt3 ligand-induced DC generation in vitro. PU.1 was also required for the parallel granulocyte-macrophage colony stimulating factor-induced DC pathway from early hematopoietic progenitors. Molecular studies demonstrated that PU.1 directly regulated Flt3 in a concentration-dependent manner, as Sfpi1(+/-) cells displayed reduced expression of Flt3 and impaired DC formation. These studies identify PU.1 as a critical regulator of both conventional and plasmacytoid DC development and provide one mechanism how altered PU.1 concentration can have profound functional consequences for hematopoietic cell development.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2014
DOI: 10.1038/NI0914-894B
Publisher: Springer Science and Business Media LLC
Date: 13-07-2022
DOI: 10.1038/S41418-022-01037-5
Abstract: High-throughput methodologies are the cornerstone of screening approaches to identify novel compounds that regulate immune cell function. To identify novel targeted therapeutics to treat immune disorders and haematological malignancies, there is a need to integrate functional cellular information with the molecular mechanisms that regulate changes in immune cell phenotype. We facilitate this goal by combining quantitative methods for dissecting complex simultaneous cell phenotypic effects with genomic analysis. This combination strategy we term Multiplexed Analysis of Cells sequencing (MAC-seq), a modified version of Digital RNA with perturbation of Genes (DRUGseq). We applied MAC-seq to screen compounds that target the epigenetic machinery of B cells and assess altered humoral immunity by measuring changes in proliferation, survival, differentiation and transcription. This approach revealed that polycomb repressive complex 2 (PRC2) inhibitors promote antibody secreting cell (ASC) differentiation in both murine and human B cells in vitro. This is further validated using T cell-dependent immunization in mice. Functional dissection of downstream effectors of PRC2 using arrayed CRISPR screening uncovered novel regulators of B cell differentiation, including Mybl1 , Myof , Gas7 and Atoh8 . Together, our findings demonstrate that integrated phenotype-transcriptome analyses can be effectively combined with drug screening approaches to uncover the molecular circuitry that drives lymphocyte fate decisions.
Publisher: Rockefeller University Press
Date: 28-03-2023
DOI: 10.1084/JEM.20222052
Abstract: “γc” cytokines are a family whose receptors share a “common-gamma-chain” signaling moiety, and play central roles in differentiation, homeostasis, and communications of all immunocyte lineages. As a resource to better understand their range and specificity of action, we profiled by RNAseq the immediate-early responses to the main γc cytokines across all immunocyte lineages. The results reveal an unprecedented landscape: broader, with extensive overlap between cytokines (one cytokine doing in one cell what another does elsewhere) and essentially no effects unique to any one cytokine. Responses include a major downregulation component and a broad Myc-controlled resetting of biosynthetic and metabolic pathways. Various mechanisms appear involved: fast transcriptional activation, chromatin remodeling, and mRNA destabilization. Other surprises were uncovered: IL2 effects in mast cells, shifts between follicular and marginal zone B cells, paradoxical and cell-specific cross-talk between interferon and γc signatures, or an NKT-like program induced by IL21 in CD8+ T cells.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.IMMUNI.2014.10.016
Abstract: B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.
Publisher: Rockefeller University Press
Date: 05-01-2004
Abstract: Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors. To investigate their in vivo role in lymphomagenesis, an IgH enhancer-driven c-myc transgene was crossed onto Apaf-1−/− and caspase-9−/− mice. Due to perinatal lethality, Eμ-myc transgenic Apaf-1−/− or caspase-9−/− fetal liver cells were used to reconstitute lethally irradiated recipient mice. Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc–induced lymphomas. Moreover, loss of Apaf-1 did not promote oncogene-induced transformation of mouse embryo fibroblasts. Thus, Apaf-1 and caspase-9 do not suppress c-myc–induced lymphomagenesis and embryo fibroblast transformation.
Publisher: EMBO
Date: 15-10-2014
Abstract: Natural killer ( NK ) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK ‐cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK ‐cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK ‐cell maturation revealed that Aiolos was required for the maturation in the spleen of CD 11b high CD 27 − NK cells. The differentiation block was intrinsic to the NK ‐cell lineage and resembled that found in mice lacking either T‐bet or Blimp1 however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK ‐cell differentiation. NK cells lacking Aiolos were strongly hyper‐reactive to a variety of NK ‐cell‐mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD 27 − NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK ‐cell maturation and function.
Publisher: American Society of Hematology
Date: 04-06-2009
DOI: 10.1182/BLOOD-2008-08-172866
Abstract: Multiple myeloma (MM) and plasmacytomas are cancers of antibody-secreting cells (ASCs). PRDM1/BLIMP1 is an essential regulator of ASC development. Histologic evidence shows that 100% of MM expresses PRDM1/BLIMP1, indicating that PRDM1/BLIMP1 is important for the development or persistence of MM. In contrast, some diffuse large B-cell lymphomas (DLBCLs) lose PRDM1 expression, suggesting that PRDM1 may act as a tumor suppressor in DLBCL. Thus, the role of PRDM1/BLIMP1 in transformation of mature B cells is unclear. We have used a plasmacytoma-prone transgenic mouse model to study the effect of Blimp1 loss on plasmacytoma prevalence, latency, and phenotype. Two possible outcomes could be envisaged: loss of Blimp1 might decrease plasmacytoma prevalence, through reduction of plasma cells, and so the number of susceptible transformation targets. Alternatively, Blimp1 may participate in the transformation process itself. Our results support the latter scenario, showing that decreasing Blimp1 dosage does not change plasma cell number in nontransgenic mice in vivo, but it significantly reduces plasmacytoma prevalence in transgenic mice. Loss of functional Blimp1 completely prevents plasmacytoma formation in this tumor model. These observations suggest that Blimp1 is limiting for plasma cell transformation and thus has potential as a target for new therapies to combat MM.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2015
DOI: 10.1038/NI0515-544D
Publisher: American Society of Hematology
Date: 19-03-2015
DOI: 10.1182/BLOOD-2014-08-594655
Abstract: Regulation of genes required for B-cell progenitor proliferation is exquisitely dependent on Moz gene dosage. Loss of one Moz allele delays the onset of MYC-driven lymphoma by 3.9-fold.
Publisher: Wiley
Date: 12-2010
Publisher: The American Association of Immunologists
Date: 08-2015
Abstract: Targeting Ags to dendritic cell (DC) surface receptors can induce a variety of responses depending on the DC type targeted, the receptor targeted, and the adjuvant used. Clec9A (DNGR-1), which is expressed by CD8+ DCs, has been shown to bind F-actin exposed on damaged cells. Targeting Ag to this receptor in mice and nonhuman primates induces strong humoral immunity even in the absence of adjuvant, a process seen for a few select DC receptors. In contrast with other receptors, however, targeting Clec9A induces long-lived, affinity-matured Ab responses that are associated with efficient CD4+ T cell responses shown to possess properties of follicular Th cells (TFH). In this article, we provide definitive evidence that Clec9A targeting promotes the development of TFH by showing that responding CD4 T cells express CXCR5, PD1, the TFH transcription factor Bcl6, and the cytokine IL-21, and that these cells localize to germinal centers. Furthermore, we extend studies from the model Ag OVA to the viral Ag glycoprotein D of HSV-1 and examine the capacity of primed TFH to form functional memory. We show that targeting glycoprotein D to Clec9A even in the absence of adjuvant induced long-lived memory CXCR5+ PD1hi CD4+ T cells that proliferated extensively upon secondary challenge and rapidly developed into effector TFH. This was associated with enhanced germinal center B cell responses and accelerated Ab production. Our study indicates that targeting Ags to Clec9A in the absence of adjuvant routinely generates TFH responses that form long-lived memory capable of robust secondary TFH responses.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.IMMUNI.2016.07.003
Abstract: Long-lived plasma cells (LLPCs) are durable antibody-producing cells that are key to immunity. Bhattacharya and colleagues find that LLPCs derive their enhanced survival capacity from a higher rate of glucose import. Some of this glucose sustains the cells through glycolysis, while the bulk is required for antibody glycosylation.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
Publisher: The American Association of Immunologists
Date: 15-02-2004
DOI: 10.4049/JIMMUNOL.172.4.2048
Abstract: IL-21 is a recently identified cytokine that stimulates mouse NK cell effector functions in vitro. In this study we demonstrate that IL-21 achieves its stimulatory effect by inducing the development of mature NK cells into a large granular lymphocyte phenotype with heightened effector function. IL-21 treatment results in increased cell size and granularity and a corresponding decrease in cell viability and proliferative potential. These cells up-regulate the expression of the inhibitory CD94-NKG2A receptor complex and the activation markers CD154 and killer cell, lectin-like-receptor G1. Surprisingly, IL-21 treatment also results in down-regulation of the pan-NK marker, NK1.1. Coinciding with these cellular changes IL-21 enhances cytolytic capacity across a spectrum of target sensitivities and induces IL-10 and IFN-γ production. In vivo treatment with IL-21 results in a very similar activation and phenotypic maturation of NK cells as well as a potent increase in NK cell-mediated anti-tumor immunity that is perforin dependent. These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance.
Publisher: Wiley
Date: 09-06-2021
DOI: 10.1111/IMR.12988
Abstract: Antibodies are an essential element of the immune response to infection, and in long‐term protection upon re‐exposure to the same micro‐organism. Antibodies are produced by plasmablasts and plasma cells, the terminally differentiated cells of the B lymphocyte lineage. These relatively rare populations, collectively termed antibody secreting cells (ASCs), have developed highly specialized transcriptional and metabolic pathways to facilitate their extraordinarily high rates of antibody synthesis and secretion. In this review, we discuss the gene regulatory network that controls ASC identity and function, with a particular focus on the processes that influence the transcription, translation, folding, modification and secretion of antibodies. We will address how ASCs have adapted their transcriptional, metabolic and protein homeostasis pathways to sustain such high rates of antibody production, and the roles that the major ASC regulators, the transcription factors, Irf4, Blimp‐1 and Xbp1, play in co‐ordinating these processes.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-03-2009
Abstract: Plasma cells represent the end stage of B-cell development and play a key role in providing an efficient antibody response, but they are also involved in numerous pathologies. Here we show that CD93, a receptor expressed during early B-cell development, is reinduced during plasma-cell differentiation. High CD93/CD138 expression was restricted to antibody-secreting cells both in T-dependent and T-independent responses as naive, memory, and germinal-center B cells remained CD93-negative. CD93 was expressed on (pre)plasmablasts lasma cells, including long-lived plasma cells that showed decreased cell cycle activity, high levels of isotype-switched Ig secretion, and modification of the transcriptional network. T-independent and T-dependent stimuli led to re-expression of CD93 via 2 pathways, either before or after CD138 or Blimp-1 expression. Strikingly, while humoral immune responses initially proceeded normally, CD93-deficient mice were unable to maintain antibody secretion and bone-marrow plasma-cell numbers, demonstrating that CD93 is important for the maintenance of plasma cells in bone marrow niches.
Publisher: The Company of Biologists
Date: 15-11-2010
DOI: 10.1242/DEV.050021
Abstract: Macrophages have been suggested to stimulate neo-lymphangiogenesis in settings of inflammation via two potential mechanisms: (1) acting as a source of lymphatic endothelial progenitor cells via the ability to transdifferentiate into lymphatic endothelial cells and be incorporated into growing lymphatic vessels and (2) providing a crucial source of pro-lymphangiogenic growth factors and proteases. We set out to establish whether cells of the myeloid lineage are important for development of the lymphatic vasculature through either of these mechanisms. Here, we provide lineage tracing evidence to demonstrate that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse, thus excluding macrophages as a source of lymphatic endothelial progenitor cells in these settings. In addition, we demonstrate that the dermal lymphatic vasculature of PU.1–/– and Csf1r–/– macrophage-deficient mouse embryos is hyperplastic owing to elevated lymphatic endothelial cell proliferation, suggesting that cells of the myeloid lineage provide signals that act to restrain lymphatic vessel calibre in the skin during development. In contrast to what has been demonstrated in settings of inflammation, macrophages do not comprise the principal source of pro-lymphangiogenic growth factors, including VEGFC and VEGFD, in the embryonic dermal microenvironment, illustrating that the sources of patterning and proliferative signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-04-2021
DOI: 10.1126/SCIIMMUNOL.ABF4432
Abstract: DC-SCRIPT is a key transcription factor controlling type 1 conventional dendritic cell fate and function.
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.SMIM.2007.12.002
Abstract: Recent advances in the identification of mouse plasma cells have enabled a more detailed assessment of their development and maintenance to be undertaken. Insertion of the gene encoding green fluorescent protein into the Blimp1 locus has allowed measurement of the efficiency and kinetics with which subsets of mature B cells generate antibody-secreting cells (ASCs) after culture with a series of mitogens, with and without co-stimulation. In vivo identification of plasma cells has allowed their phenotype to be defined and changes in their frequency as a result of aging and immunisation to be monitored. This new approach has allowed also a more precise definition of the genetic program activated in plasma cell differentiation. In this review we cover these aspects of plasma cell development with a particular emphasis on the B-cell subsets giving rise to the plasma cells and to their maintenance once formed.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-09-2021
DOI: 10.1126/SCIIMMUNOL.ABF7268
Abstract: PRC2 is essential for the self-renewal of tissue-resident macrophages but dispensable for dendritic cell development and function.
Publisher: Rockefeller University Press
Date: 02-05-2005
DOI: 10.1084/JEM.20050075
Abstract: Although the transcription factor PU.1 is essential for fetal lymphomyelopoiesis, we unexpectedly found that elimination of the gene in adult mice allowed disturbed hematopoiesis, dominated by granulocyte production. Impaired production of lymphocytes was evident in PU.1-deficient bone marrow (BM), but myelocytes and clonogenic granulocytic progenitors that are responsive to granulocyte colony-stimulating factor or interleukin-3 increased dramatically. No identifiable common lymphoid or myeloid progenitor populations were discernable by flow cytometry however, clonogenic assays suggested an overall increased frequency of blast colony-forming cells and BM chimeras revealed existence of long-term self-renewing PU.1-deficient cells that required PU.1 for lymphoid, but not granulocyte, generation. PU.1 deletion in granulocyte-macrophage progenitors, but not in common myeloid progenitors, resulted in excess granulocyte production this suggested specific roles of PU.1 at different stages of myeloid development. These findings emphasize the distinct nature of adult hematopoiesis and reveal that PU.1 regulates the specification of the multipotent lymphoid and myeloid compartments and restrains, rather than promotes, granulopoiesis.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 19-07-2013
DOI: 10.1038/NI0813-877C
Publisher: Springer Science and Business Media LLC
Date: 19-07-2013
DOI: 10.1038/NI0813-877B
Publisher: American Society for Clinical Investigation
Date: 15-08-2016
DOI: 10.1172/JCI87828
Publisher: Wiley
Date: 12-2006
Abstract: Unlike early B/T cell development, NK cell lineage commitment is not well understood, with a major limitation being the lack of a robust culture system to assay NK cell progenitors. Here we have exploited the multi-lineage potential of Pax5(-/-) pro-B cells to establish an effective system to direct differentiation of progenitors into the NK cell lineage. Cultivation of Pax5(-/-) pro-B cells on OP9 cells expressing the Notch ligand Delta-Like1 (OP9-DL1) in the presence of IL-7 efficiently induced T and NK cell potential. For NK cells, Notch was only transiently required, as prolonged signaling decreased NK and increased T cell development. Pure NK cell populations could be obtained by the culture of these Notch signal-experienced cells onto OP9 stroma and IL-15. A similar transient exposure to Notch was also compatible with the differentiation of NK cells from hematopoietic progenitors, while sustained Notch signaling impaired NK cell generation. Pax5(-/-) pro-B cell-derived NK cells were cytotoxic, secreted cytokines and expressed all the expected NK cell-specific surface markers examined except the Ly49 family, a phenotype similar to fetal NK cells. These data indicate that Notch signaling induces T/NK cell differentiation in Pax5(-/-) pro-B cells that is strikingly similar to early thymopoiesis.
Publisher: Elsevier BV
Date: 02-2019
Publisher: Springer Science and Business Media LLC
Date: 19-01-2015
DOI: 10.1038/NI.3085
Abstract: Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2022
DOI: 10.1038/S41467-022-32485-9
Abstract: CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse ( dCas9a-SAM KI ) for inducing gene expression in vivo and in vitro. Using dCas9a-SAM KI primary lymphocytes, we induce B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivate pro-survival BCL-2 in Eµ-Myc T/+ dCas9a-SAM KI/+ haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly develop lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas are highly sensitive to the BCL-2 inhibitor venetoclax. We perform genome-wide activation screens in these lymphoma cells and find a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the potential of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 31-01-2021
DOI: 10.1101/2021.01.29.428877
Abstract: PAX5 is the master transcription factor controlling B cell identity. In humans, mutations in PAX5 account for 30% of B cell acute lymphoblastic leukemia (B-ALL) cases. Investigating the causal effects of PAX5 mutations has however been difficult due to the premature lethality of Pax5 −/− mice. Here we describe a novel mouse strain with a premature STOP mutation in Pax5 (Y351*) that produces a truncated protein and reduction in protein function, yet still allows for some B cell development to occur. A population of uncommitted and multipotent CD19 + B220 − B cells develops in the bone marrow of homozygous mice leading to the development of B-ALL. We show that the tumors frequently acquire secondary mutations in Jak3 , and Ptpn11 highlighting key pathways interacting with PAX5 during malignant transformation. Analysis of the PAX5 Y351* mice provide insight not only into the functional consequence of reduced PAX5 activity on B cell development and identity, but also provides an avenue in which to study PAX5-driven B-ALL in mice. Reduction in PAX5 function in mice induces the development of uncommitted B cells that have multipotent and malignant potential.
Publisher: American Society for Microbiology
Date: 15-03-2019
DOI: 10.1128/JVI.01795-18
Abstract: Neutralizing antibody response is the best-known correlate of long-term protective immunity for most of the currently licensed clinically effective viral vaccines. However, the host immune and viral factors that are critical for the induction of robust and durable antiviral humoral immune responses are not well understood. Our study provides insight into the dynamics of key cellular mediators of germinal center reaction during live virus infections and the influence of viral replicative capacity on the magnitude of antiviral antibody response and effector function. The significance of our study lies in two key findings. First, the systemic spread of even poorly replicating or nonreplicating viruses to mimic the spread of antigens from replicating viruses due to escalating antigen concentration is fundamental to the induction of durable antibody responses. Second, the T FH :T FR ratio may be used as an early predictor of protective antiviral humoral immune responses long before memory responses are generated.
Publisher: The American Association of Immunologists
Date: 02-2017
Abstract: CD4 T cells can differentiate into multiple effector subsets, including ThCTL that mediate MHC class II–restricted cytotoxicity. Although CD4 T cell–mediated cytotoxicity has been reported in multiple viral infections, their characteristics and the factors regulating their generation are unclear, in part due to a lack of a signature marker. We show in this article that, in mice, NKG2C/E identifies the ThCTL that develop in the lung during influenza A virus infection. ThCTL express the NKG2X/CD94 complex, in particular the NKG2C/E isoforms. NKG2C/E+ ThCTL are part of the lung CD4 effector population, and they mediate influenza A virus–specific cytotoxic activity. The phenotype of NKG2C/E+ ThCTL indicates they are highly activated effectors expressing high levels of binding to P-selectin, T-bet, and Blimp-1, and that more of them secrete IFN-γ and readily degranulate than non-ThCTL. ThCTL also express more cytotoxicity-associated genes including perforin and granzymes, and fewer genes associated with recirculation and memory. They are found only at the site of infection and not in other peripheral sites. These data suggest ThCTL are marked by the expression of NKG2C/E and represent a unique CD4 effector population specialized for cytotoxicity.
Publisher: Cold Spring Harbor Laboratory
Date: 15-04-2006
DOI: 10.1101/GAD.1396206
Abstract: Early B-lymphopoiesis requires the growth-factor receptors, IL-7R and Flt3, and the activity of a number of transcription factors. One factor, Pax5, is required for commitment to the B-cell lineage, although the molecular mechanism by which this occurs is unknown. We demonstrate here that an important function of Pax5 is to repress Flt3 transcription in B-cell progenitors, as Pax5-deficient pro-B cells express abundant Flt3 that is rapidly silenced upon the reintroduction of Pax5, whereas enforced expression of Flt3 in wild-type progenitors significantly impairs B-cell development. These findings demonstrate that the repression of Flt3 by Pax5 is essential for normal B-lymphopoiesis.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2021
Publisher: Oxford University Press (OUP)
Date: 11-01-2012
DOI: 10.1111/J.1365-2249.2011.04496.X
Abstract: The immunomodulatory effects of probiotics were assessed following exposure of normal peripheral blood mononuclear cells (PBMC), cord blood cells and the spleen-derived monocyte/macrophage cell line CRL-9850 to Lactobacillus acidophilus LAVRI-A1, Lb. rhamnosus GG, exopolysaccharides (EPS)-producing Streptococcus thermophilus St1275, Bifidobacteriun longum BL536, B. lactis B94 and Escherichia coli TG1 strains. The production of a panel of pro- and anti-inflammatory cytokines by PBMC following bacterial stimulation was measured, using live, heat-killed or mock gastrointestinal tract (GIT)-exposed bacteria, and results show that (i) all bacterial strains investigated induced significant secretion of pro- and anti-inflammatory cytokines from PBMC-derived monocytes/macrophages and (ii) cytokine levels increased relative to the expansion of bacterial cell numbers over time for cells exposed to live cultures. Bifidobacteria and S. thermophilus stimulated significant concentrations of transforming growth factor (TGF)-β, an interleukin necessary for the differentiation of regulatory T cells (Treg)/T helper type 17 (Th17) cells and, as such, the study further examined the induction of Th17 and Treg cells after PBMC exposure to selected bacteria for 96 h. Data show a significant increase in the numbers of both cell types in the exposed populations, measured by cell surface marker expression and by cytokine production. Probiotics have been shown to induce cytokines from a range of immune cells following ingestion of these organisms. These studies suggest that probiotics' interaction with immune-competent cells produces a cytokine milieu, exerting immunomodulatory effects on local effector cells, as well as potently inducing differentiation of Th17 and Treg cells.
Publisher: Rockefeller University Press
Date: 18-10-2004
DOI: 10.1084/JEM.20040973
Abstract: Plasma cells comprise a population of terminally differentiated B cells that are dependent on the transcriptional regulator B lymphocyte–induced maturation protein 1 (Blimp-1) for their development. We have introduced a gfp reporter into the Blimp-1 locus and shown that heterozygous mice express the green fluorescent protein in all antibody-secreting cells (ASCs) in vivo and in vitro. In vitro, these cells display considerable heterogeneity in surface phenotype, immunoglobulin secretion rate, and Blimp-1 expression levels. Importantly, analysis of in vivo ASCs induced by immunization reveals a developmental pathway in which increasing levels of Blimp-1 expression define developmental stages of plasma cell differentiation that have many phenotypic and molecular correlates. Thus, maturation from transient plasmablast to long-lived ASCs in bone marrow is predicated on quantitative increases in Blimp-1 expression.
Publisher: Cold Spring Harbor Laboratory
Date: 05-2006
DOI: 10.1101/GAD.1382606
Abstract: Monocytic leukemia zinc finger protein (MOZ), a transcriptional coactivator and member of the MYST family of histone acetyltransferases, is the target of recurrent translocations in acute myeloid leukemia. Since genes associated with translocations in leukemia are typically important regulators of blood formation, we investigated if Moz has a role in normal hematopoiesis. We generated mice carrying a mutation in the Moz gene. Homozygous Moz mutant mice died at birth. Moz mutant fetal liver hematopoietic cells were incapable of contributing to the hematopoietic system of recipients after transplantation. We observed profound defects in the stem cell compartment of Moz -deficient mice. Progenitors of all lineages were reduced in number. However, blood cell lineage commitment was unaffected. Together, these results show that Moz is essential for a fundamental property of hematopoietic stem cells, the ability to reconstitute the hematopoietic system of a recipient after transplantation and that Moz is specifically required in the stem cell compartment.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.SEMCDB.2014.02.001
Abstract: Langerhans cells (LCs) are the unique antigen-presenting cell of the epidermis. LCs have long been depicted in textbooks as the archetypical dendritic cell that alerts the immune system upon pathogen induced skin barrier breakage, however recent findings argue instead for a more tolerogenic function. While the LCs that populate the epidermis in steady-state arise from progenitors that seed the skin during embryogenesis, it is now apparent that a second pathway generating LCs from a bone marrow derived progenitor is active in inflammatory settings. This review emphasizes the determinants underpinning the establishment of the LC network in steady-state and under inflammatory conditions, as well as the transcriptional machinery governing their differentiation. The dual origin of LCs raises important questions about the functional differences between these subsets in balancing the epidermal immune response between immunity and tolerance.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2020
DOI: 10.1038/S41467-020-16828-Y
Abstract: B lymphoid development is initiated by the differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating mature B cells. This highly regulated process generates clonal immunological ersity via recombination of immunoglobulin V, D and J gene segments. While several transcription factors that control B cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene ( Erg ) is essential for early B lymphoid differentiation. Erg initiates a transcriptional network involving the B cell lineage defining genes, Ebf1 and Pax5 , which directly promotes expression of key genes involved in V(D)J recombination and formation of the B cell receptor. Complementation of Erg deficiency with a productively rearranged immunoglobulin gene rescued B lineage development, demonstrating that Erg is an essential and stage-specific regulator of the gene regulatory network controlling B lymphopoiesis.
Publisher: Springer Science and Business Media LLC
Date: 04-1999
DOI: 10.1038/7720
Abstract: The developmental control genes of the Pax family are frequently associated with mouse mutants and human disease syndromes. The function of these transcription factors is sensitive to gene dosage, as mutation of one allele or a modest increase in gene number results in phenotypic abnormalities. Pax5 has an important role in B-cell and midbrain development. By following the expression of in idual Pax5 alleles at the single-cell level, we demonstrate here that Pax5 is subject to allele-specific regulation during B-lymphopoiesis. Pax5 is predominantly transcribed from only one allele in early progenitors and mature B cells, whereas it switches to a biallelic transcription mode in immature B cells. The allele-specific regulation of Pax5 is stochastic, reversible, independent of parental origin and correlates with synchronous replication, in contrast with imprinted and other monoallelically expressed genes. As a consequence, B-lymphoid tissues are mosaics with respect to the transcribed Pax5 allele, and thus mutation of one allele in heterozygous mice results in deletion of the cell population expressing the mutant allele due to loss of Pax5 function at the single-cell level. Similar allele-specific regulation may be a common mechanism causing the haploinsufficiency and frequent association of other Pax genes with human disease.
Publisher: Wiley
Date: 15-10-2019
Abstract: Antibodies are an essential component of our immune system, underpinning the effectiveness of both the primary immune response to microbial pathogens and the protective and long‐lived immunity against re‐challenge. All antibodies are produced by relatively rare populations of plasmablasts and plasma cells, collectively termed antibody‐secreting cells (ASCs). It is now apparent that ASCs are unique in the body in terms of their gene expression program and metabolic pathways that enable these cells to have an extraordinary rate of immunoglobulin gene transcription, translation, assembly and secretion. In this review we will discuss the cellular, metabolic and molecular specialization that allows ASCs to maintain such high rates of antibody production, in some cases for the life of the in idual. Throughout the review we will link these exquisite cellular and molecular adaptations to the major regulators of ASC gene expression, in an attempt to define how the ASC phenotype and function is genetically programmed.
Publisher: Massachusetts Medical Society
Date: 03-01-2008
Publisher: Springer Science and Business Media LLC
Date: 07-03-2016
DOI: 10.1038/NI.3410
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.CELREP.2015.12.006
Abstract: Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2008
DOI: 10.1007/S10875-007-9151-6
Abstract: The body tends to maintain a relatively constant number of peripheral T cells, a phenomenon termed T cell homeostasis. Homeostasis is controlled by the coordinated activity of extrinsic regulation, most notably through cytokines of the common gamma chain (cgammaC) family and intrinsic regulation by transcription factors. Whereas the former mechanism has been extensively studied and is relatively well characterized, the transcription factors that govern the homeostasis of late-stage effector and memory T cells have been less well defined but include regulators such as T-bet, Eomes, Bcl6, and Id2. The transcriptional repressor, Blimp-1 is well known as a master regulator of the terminal differentiation of B cells into antibody secreting plasma cells. Recent experiments have now revealed that Blimp-1 is also a key regulator of T cell differentiation. Blimp-1 is expressed in differentiated effector T cells and controls their homeostasis. Interestingly, Blimp-1 expression is controlled by the same cgammaC cytokines that regulate T cell homeostasis suggesting a direct link between the extrinsic and intrinsic arms of the process.
Publisher: EMBO
Date: 21-02-2017
Abstract: Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone‐H3 (H3K27me3) as part of the polycomb repressive complex 2 ( PRC 2) together with Suz12 and Eed. However, Ezh2 can also modify non‐histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin‐independent role of Ezh2 during T‐cell development and immune homeostasis. T‐cell‐specific depletion of Ezh2 induces a pronounced expansion of natural killer T ( NKT ) cells, although Ezh2‐deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC 2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF , leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2‐deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin‐independent function of Ezh2 that impacts on the development of the immune system.
Publisher: Wiley
Date: 14-08-2014
DOI: 10.1111/IMR.12207
Abstract: The multiple lineages and differentiation states that constitute the T-cell compartment all derive from a common thymic precursor. These distinct transcriptional states are maintained both in time and after multiple rounds of cell ision by the concerted actions of a small set of lineage-defining transcription factors that act in conjunction with a suite of chromatin-modifying enzymes to activate, repress, and fine-tune gene expression. These chromatin modifications collectively provide an epigenetic code that allows the stable and heritable maintenance of the T-cell phenotype. Recently, it has become apparent that the epigenetic code represents a therapeutic target for a variety of immune cell disorders, including lymphoma and acute and chronic inflammatory diseases. Here, we review the recent advances in epigenetic regulation of gene expression, particularly as it relates to the T-cell differentiation and function.
Publisher: Wiley
Date: 1994
DOI: 10.1046/J.1471-4159.1994.62010001.X
Abstract: Kainate is a potent neuroexcitatory agent its neurotoxicity is thought to be mediated by an ionotropic receptor with a nanomolar affinity for kainate. In this report, we describe the cloning of a cDNA encoding a human glutamate ionotropic receptor subunit protein from a human hippoc al library. This cDNA, termed humEAA1, is most closely related to rat and human cDNAs for kainate receptor proteins and, when expressed in COS or Chinese hamster ovary cells, is associated with high-affinity kainate receptor binding. We have successfully established cell lines stably expressing humEAA1. This is the first report of establishment of stable cell lines expressing a glutamate receptor subunit. The relative potency of compounds for displacing [3H]kainate binding of humEAA1 receptors expressed in these stable cell lines was kainate > quisqualate > domoate > L-glutamate >> (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid > dihydrokainate > 6,7-dinitroquinoxaline-2,3-dione > 6-cyano-7-nitroquinoxaline-2,3-dione. Homooligomeric expression of humEAA1 does not appear to elicit ligand-gated ion channel activity. Nevertheless, the molecular structure and pharmacological characterization of high-affinity kainate binding of the humEAA1 expressed in the stable cell line (ppEAA1-16) suggest that the humEAA1 is a subunit protein of a human kainate receptor complex.
Publisher: Rockefeller University Press
Date: 18-11-2013
DOI: 10.1084/JEM.20130930
Abstract: Langerhans cells (LCs) are the unique dendritic cells found in the epidermis. While a great deal of attention has focused on defining the developmental origins of LCs, reports addressing the transcriptional network ruling their differentiation remain sparse. We addressed the function of a group of key DC transcription factors—PU.1, ID2, IRF4, and IRF8—in the establishment of the LC network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow–derived LCs. PU.1 controls LC differentiation by regulating the expression of the critical TGF-β responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-β–dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2022
Publisher: Wiley
Date: 28-12-2021
DOI: 10.1111/IMCB.12518
Abstract: In a new study, researchers have identified a new population of type 2 conventional dendritic cells in the skin that depend on IL-13 and promote Th2 mediated immunity.
Publisher: American Society of Hematology
Date: 08-04-2010
DOI: 10.1182/BLOOD-2009-08-239210
Abstract: c-Myb is a transcription factor with functions in many hematopoietic lineages. c-Myb–deficient mice display reduced numbers of B cells however, it is unknown what role c-Myb plays in B lymphopoiesis because no critical target genes have been identified in the B-cell lineage. We demonstrate that conditional deletion of c-Myb in B-cell progenitors completely abolishes B-cell development. c-Myb is required for lymphoid progenitors to respond to the cytokines interleukin-7 and thymic stromal lymphopoietin in the absence of sufficient c-Myb activity, mice display a B lymphopenia that closely resembles that observed in interleukin-7 receptor α–deficient animals. Analysis of the multipotent progenitor compartment indicates that c-Myb is also required for up-regulation of multiple lymphoid-associated genes, including Il7r, and for the subsequent development of the common lymphoid progenitor population. These data show that c-Myb plays a critical role in the regulatory pathways governing lymphoid specification and early B-cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 10-04-2015
DOI: 10.1038/NCOMMS7750
Abstract: During immune reactions, functionally distinct B-cell subsets are generated by stochastic processes, including class-switch recombination (CSR) and plasma cell differentiation (PCD). In this study, we show a strong association between in idual B-cell fates and mitochondrial functions. CSR occurs specifically in activated B cells with increased mitochondrial mass and membrane potential, which augment mitochondrial reactive oxygen species (mROS), whereas PCD occurs in cells with decreased mitochondrial mass and potential. These events are consequences of initial slight changes in mROS in mitochondria high B-cell populations. In CSR-committed cells, mROS attenuates haeme synthesis by inhibiting ferrous ion addition to protoporphyrin IX, thereby maintaining Bach2 function. Reduced mROS then promotes PCD by increasing haeme synthesis. In PCD-committed cells, Blimp1 reduces mitochondrial mass, thereby reducing mROS levels. Identifying mROS as a haeme synthesis regulator increases the understanding of mechanisms regulating haeme homeostasis and cell fate determination after B-cell activation.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.IMMUNI.2006.11.010
Abstract: Intravenous immune globulin (IVIG) suppresses autoantibody-mediated inflammation by inducing and activating the inhibitory Fc receptor FcgammaRIIb and downstream negative signaling pathways. We investigated the effects of IVIG on cellular responses to interferon-gamma (IFN-gamma), a potent macrophage activator that exacerbates inflammation. Our study showed that IVIG blocked IFN-gamma signaling and IFN-gamma-induced gene expression and suppressed IFN-gamma function in vivo during immune responses to Listeria monocytogenes and in an IFN-gamma-enhanced model of immune thrombocytopenic purpura. The mechanism of inhibition of IFN-gamma signaling was suppression of expression of the IFNGR2 subunit of the IFN-gamma receptor. The inhibitory effect of IVIG was mediated at least in part by soluble immune complexes and was dependent on FcgammaRIII but independent of FcgammaRIIb. These results reveal an unexpected inhibitory role for the activating FcgammaRIII in mediating suppression of IFN-gamma signaling and suggest that inhibition of macrophage responses to IFN-gamma contributes to the anti-inflammatory properties of IVIG.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2016
DOI: 10.1038/NI.3348
Publisher: The American Association of Immunologists
Date: 04-2007
DOI: 10.4049/JIMMUNOL.178.7.4104
Abstract: The transcriptional repressor Blimp-1 (B lymphocyte-induced maturation protein 1) has been described as a “master regulator” of B cell differentiation into Ab-secreting cells (ASCs). Although there is mounting evidence for the importance and necessity of Blimp-1 in plasma cell development, there is uncertainty as to the role it plays in B cell differentiation of B cell subsets and the way in which it may interact with other transcription factors such as Pax5 and Bcl6 during ASC differentiation. Using a mouse expressing GFP under the control of the Blimp-1 regulatory elements (Blimp-1GFP/+), we examined the kinetics of Blimp-1 up-regulation in purified B cell subsets following activation. B1 cells showed the most rapid and pronounced up-regulation of Blimp-1 in response to the mitogens tested, followed by marginal zone B cells and then conventional B2 cells. Interestingly, only B1 cells substantially up-regulated Blimp-1 expression in response to CpG. B1 cells secreted negligible Ig upon isolation but were able to up-regulate Blimp-1 and initiate Ig secretion within 28 h of stimulation. Also of interest, B1 cells have a transcriptional factor profile that is intermediate between a naive B cell and an ASC, indicative of the semiactivated state of B1 cells. Transferred naive Blimp-1GFP/+ B1 and B2 cells both gave rise to ASCs in the bone marrow, suggesting no intrinsic barriers to B1 cell entry into the long-lived ASC compartment.
Publisher: Rockefeller University Press
Date: 17-01-2005
DOI: 10.1084/JEM.20041535
Abstract: PU.1 is an Ets family transcription factor that is essential for fetal liver hematopoiesis. We have generated a PU.1gfp reporter strain that allowed us to examine the expression of PU.1 in all hematopoietic cell lineages and their early progenitors. Within the bone marrow progenitor compartment, PU.1 is highly expressed in the hematopoietic stem cell, the common lymphoid progenitor, and a proportion of common myeloid progenitors (CMPs). Based on Flt3 and PU.1 expression, the CMP could be ided into three subpopulations, Flt3+ PU.1hi, Flt3− PU.1hi, and Flt3− PU.1lo CMPs. Colony-forming assays and in vivo lineage reconstitution demonstrated that the Flt3+ PU.1hi and Flt3− PU.1hi CMPs were efficient precursors for granulocyte/macrophage progenitors (GMPs), whereas the Flt3− PU.1lo CMPs were highly enriched for committed megakaryocyte/erythrocyte progenitors (MEPs). CMPs have been shown to rapidly differentiate into GMPs and MEPs in vitro. Interestingly, short-term culture revealed that the Flt3+ PU.1hi and Flt3− PU.1hi CMPs rapidly became CD16/32high (reminiscent of GMPs) in culture, whereas the Flt3− PU.1lo CMPs were the immediate precursors of the MEP. Thus, down-regulation of PU.1 expression in the CMP is the first molecularly identified event associated with the restriction of differentiation to erythroid and megakaryocyte lineages.
Publisher: The American Association of Immunologists
Date: 04-2013
Abstract: B cells are exposed to high levels of CD40 ligand (CD40L, CD154) in chronic inflammatory diseases. In addition, B cells expressing both CD40 and CD40L have been identified in human diseases such as autoimmune diseases and lymphoma. However, how such constitutively CD40–activated B cells under inflammation may impact on T cell response remains unknown. Using a mouse model in which B cells express a CD40L transgene (CD40LTg) and receive autocrine CD40/CD40L signaling, we show that CD40LTg B cells stimulated memory-like CD4 and CD8 T cells to express IL-10. This IL-10 expression by CD8 T cells was dependent on IFN-I and programmed cell death protein 1, and was critical for CD8 T cells to counterregulate their overactivation. Furthermore, adoptive transfer of naive CD8 T cells in RAG-1−/− mice normally induces colitis in association with IL-17 and IFN-γ cytokine production. Using this model, we show that adoptive cotransfer of CD40LTg B cells, but not wild-type B cells, significantly reduced IL-17 response and regulated colitis in association with IL-10 induction in CD8 T cells. Thus, B cells expressing CD40L can be a therapeutic goal to regulate inflammatory CD8 T cell response by IL-10 induction.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2011
DOI: 10.1038/NI.2019
Abstract: Humoral immunity requires interaction between specialized populations of B cells and CD4(+) T cells, called follicular helper T cells (T(FH) cells), in the germinal center (GC) to produce memory B cells and long-lived plasma cells. Molecular crosstalk between GC B cells and T(FH) cells influences the survival, proliferation and differentiation of each cell type. This pairing of GC B cells and T(FH) cells also occurs at the transcriptional level as the Bcl-6–IRF4–Blimp-1 axis, which is crucial for B cell differentiation, is also essential for the T(FH) cell identity. Less is known about the memory B cells that arise from the GC pool, as they seem to be distinctly 'programmed' on the basis of their antigen receptor affinity to enter the long-lived memory pool.
Publisher: Springer International Publishing
Date: 2014
DOI: 10.1007/82_2014_377
Abstract: The differentiation of early B cell progenitors is controlled by multiple transcriptional regulators and growth-factor receptors. The triad of DNA-binding proteins, E2A, EBF1, and PAX5 is critical for both the early specification and commitment of B cell progenitors, while a larger number of secondary determinants, such as members of the Ikaros, ETS, Runx, and IRF families have more direct roles in promoting stage-specific pre-B gene-expression program. Importantly, it is now apparent that mutations in many of these transcription factors are associated with the progression to acute lymphoblastic leukemia. In this review, we focus on recent studies that have shed light on the transcriptional hierarchy that controls efficient B cell commitment and differentiation as well as focus on the oncogenic consequences of the loss of many of the same factors.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2016
DOI: 10.1038/NI.3349
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
DOI: 10.1038/S41467-017-01605-1
Abstract: Humoral immunity requires B cells to respond to multiple stimuli, including antigen, membrane and soluble ligands, and microbial products. Ets family transcription factors regulate many aspects of haematopoiesis, although their functions in humoral immunity are difficult to decipher as a result of redundancy between the family members. Here we show that mice lacking both PU.1 and SpiB in mature B cells do not generate germinal centers and high-affinity antibody after protein immunization. PU.1 and SpiB double-deficient B cells have a survival defect after engagement of CD40 or Toll-like receptors (TLR), despite paradoxically enhanced plasma cell differentiation. PU.1 and SpiB regulate the expression of many components of the B cell receptor signaling pathway and the receptors for CD40L, BAFF and TLR ligands. Thus, PU.1 and SpiB enable B cells to appropriately respond to environmental cues.
Publisher: American Medical Association (AMA)
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 26-08-2019
Publisher: The American Association of Immunologists
Date: 12-2010
Abstract: Although NK cells are well known for their cytotoxic functions, they also produce an array of immunoregulatory cytokines and chemokines. During an immune response, NK cells are exposed to complex combinations of cytokines that influence their differentiation and function. In this study, we have examined the phenotypic and functional consequences of exposing mouse NK cells to IL-4, IL-12, IL-15, IL-18, and IL-21 and found that although all factors induced signs of maturation, characterized by decreased proliferation and IFN-γ secretion, distinct combinations induced unique cytokine secretion profiles. In contrast, the immunosuppressive factors IL-10 and TGF-β had little direct effect on NK cell effector functions. Sustained IL-18 signals resulted in IL-13 and GM-CSF production, whereas IL-12 and IL-21 induced IL-10 and TNF-α. Surprisingly, with the exception of IL-21, all cytokines suppressed cytotoxic function of NK cells at the expense of endogenous cytokine production suggesting that “helper-type” NK cells were generated. The cytokine signals also profoundly altered the cell surface phenotype of the NK cells—a striking ex le being the downregulation of the activating receptor NKG2D by IL-4 that resulted in decreased NKG2D-dependent killing. IL-4 exposure also modulated NKG2D expression in vivo suggesting it is functionally important during immune responses. This study highlights the plasticity of NK cell differentiation and suggests that the relative abundance of cytokines at sites of inflammation will lead to erse outcomes in terms of NK cell phenotype and interaction with the immune system.
Publisher: Wiley
Date: 13-11-2007
Abstract: The activity of the transcription factor paired box gene 5 (Pax5) is essential for many aspects of B lymphopoiesis including the initial commitment to the lineage, immunoglobulin rearrangement, pre-B cell receptor signalling and maintaining cell identity in mature B cells. Deregulated or reduced Pax5 activity has also been implicated in B-cell malignancies both in human disease and mouse models. Candidate gene approaches and biochemical analysis have revealed that Pax5 regulates B lymphopoiesis by concurrently activating B cell-specific gene expression as well as repressing the expression of genes, many of which are associated with non-B cell lineages. These studies have been recently complemented with more exhaustive microarray studies, which have identified and validated a large panel of Pax5 target genes. These target genes reveal a gene regulatory network, with Pax5 at its centre that controls the B-cell gene expression programme.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2007
DOI: 10.1038/NI1487
Publisher: Rockefeller University Press
Date: 14-02-2005
DOI: 10.1084/JEM.20042060
Abstract: Immunization with a T cell–dependent antigen elicits production of specific memory B cells and antibody-secreting cells (ASCs). The kinetic and developmental relationships between these populations and the phenotypic forms they and their precursors may take remain unclear. Therefore, we examined the early stages of a primary immune response, focusing on the appearance of antigen-specific B cells in blood. Within 1 wk, antigen-specific B cells appear in the blood with either a memory phenotype or as immunoglobulin (Ig)G1 ASCs expressing blimp-1. The memory cells have mutated VH genes respond to the chemokine CXCL13 but not CXCL12, suggesting recirculation to secondary lymphoid organs uniformly express B220 show limited differentiation potential unless stimulated by antigen and develop independently of blimp-1 expression. The antigen-specific IgG1 ASCs in blood show affinity maturation paralleling that of bone marrow ASCs, raising the possibility that this compartment is established directly by blood-borne ASCs. We find no evidence for a blimp-1–expressing preplasma memory compartment, suggesting germinal center output is restricted to ASCs and B220+ memory B cells, and this is sufficient to account for the process of affinity maturation.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2013
DOI: 10.1038/NRI3385
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.IMMUNI.2007.05.010
Abstract: The expression of lineage-associated genes, as well as the survival and expansion of committed B cell progenitors, is controlled by multiple transcriptional regulators and growth-factor receptors. Whereas certain DNA-binding proteins, such as Ikaros and PU.1, are required primarily for the formation of more primitive lymphoid progenitors, other factors such as E2A and EBF1 have more direct roles in specifying the B cell-specific gene-expression program. Further, Pax5 functions to promote B cell commitment by repressing lineage-inappropriate gene expression and reinforcing B cell-specific gene expression. In this review, we focus on recent studies that have revealed that instead of a simple transcriptional hierarchy, efficient B cell commitment and differentiation requires the combinatorial activity of multiple transcription factors in a complex gene regulatory network.
Publisher: Springer Science and Business Media LLC
Date: 11-2006
DOI: 10.1038/NI1106-1134
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 17-05-2011
Publisher: Springer Science and Business Media LLC
Date: 25-01-2012
DOI: 10.1038/NRI3149
Abstract: Specialized subsets of dendritic cells (DCs) provide a crucial link between the innate and adaptive immune responses. The genetic programme that coordinates these distinct DC subsets is controlled by both cytokines and transcription factors. The initial steps in DC specification occur in the bone marrow and result in the generation of precursors committed to either the plasmacytoid or conventional DC pathways. DCs undergo further differentiation and lineage ersification in peripheral organs in response to local environmental cues. In this Review, we discuss new evidence regarding the coordination of the specification and commitment of precursor cells to different DC subsets and highlight the ensemble of transcription factors that control these processes.
Publisher: The American Association of Immunologists
Date: 11-2014
Publisher: Wiley
Date: 10-02-2022
DOI: 10.1111/IMCB.12521
Abstract: The role of RNA‐binding proteins of the CCCH‐containing family in regulating proinflammatory cytokine production and inflammation is increasingly recognized. We have identified ZC3H12C (Regnase‐3) as a potential post‐transcriptional regulator of tumor necrosis factor expression and have investigated its role in vivo by generating Zc3h12c ‐deficient mice that express green fluorescent protein instead of ZC3H12C. Zc3h12c ‐deficient mice develop hypertrophic lymph nodes. In the immune system, ZC3H12C expression is mostly restricted to the dendritic cell (DC) populations, and we show that DC‐restricted ZC3H12C depletion is sufficient to cause lymphadenopathy. ZC3H12C can regulate Tnf messenger RNA stability via its RNase activity in vitro, and we confirmed the role of Tnf in the development of lymphadenopathy. Finally, we found that loss of ZC3H12C did not impact the outcome of skin inflammation in the imiquimod‐induced murine model of psoriasis, despite Zc3h12c being identified as a risk factor for psoriasis susceptibility in several genome‐wide association studies. Our data suggest a role for ZC3H12C in DC‐driven skin homeostasis.
Publisher: Informa UK Limited
Date: 2021
Publisher: American Society of Hematology
Date: 08-2008
Publisher: Springer Science and Business Media LLC
Date: 15-10-2018
DOI: 10.1038/S41590-018-0234-8
Abstract: Recent studies have elucidated cell-lineage-specific three-dimensional genome organization however, how such specific architecture is established or maintained is unclear. We hypothesized that lineage-defining transcription factors maintain cell identity via global control of genome organization. These factors bind many genomic sites outside of the genes that they directly regulate and thus are potentially implicated in three-dimensional genome organization. Using chromosome-conformation-capture techniques, we show that the transcription factor Paired box 5 (Pax5) is critical for the establishment and maintenance of the global lineage-specific architecture of B cells. Pax5 was found to supervise genome architecture throughout B cell differentiation, until the plasmablast stage, in which Pax5 is naturally silenced and B cell-specific genome structure is lost. Crucially, Pax5 did not rely on ongoing transcription to organize the genome. These results implicate sequence-specific DNA-binding proteins in global genome organization to establish and maintain lineage fidelity.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.CELREP.2016.03.066
Abstract: Plasmacytoid dendritic cells (pDCs) represent a unique immune cell type that responds to viral nucleic acids through the rapid production of type I interferons. Within the hematopoietic system, the transcription factor RUNX2 is exclusively expressed in pDCs and is required for their peripheral homeostasis. Here, we show that RUNX2 plays an essential role in promoting pDC localization and function. RUNX2 is required for the appropriate expression of the integrin-mediated adhesion machinery, as well as for the down-modulation of the chemokine receptor CXCR4, which allows pDC egress into the circulation. RUNX2 also facilitates the robust response to viral infection through the control of IRF7, the major regulator of type I interferon production. Mice lacking one copy of Runx2 have reduced numbers of peripheral pDCs and IFN-α expression, which might contribute to the reported difficulties of in iduals with cleidocranial dysplasia, who are haploinsufficient for RUNX2, to clear viral infections.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2013
DOI: 10.1007/S00018-013-1420-3
Abstract: The germinal center (GC) reaction is critical for humoral immunity, but also contributes adversely to a variety of autoimmune diseases. While the major protective function of GCs is mediated by plasma cells and memory B cells, follicular helper T (TFH) cells represent a specialized T cell subset that provides essential help to the antigen-specific B cells in the form of membrane-bound ligands and secreted factors such as IL-21. Recent studies have revealed that TFH cells are capable of considerable functional ersity as well as possessing the ability to form memory cells. The molecular basis of this plasticity and heterogeneity is only now emerging. It has also become apparent that several other populations of follicular T cells exist, including natural killer T cells and regulatory T cells. In this review we will discuss the function of follicular T cells and interaction of these populations within the GC response.
Publisher: The Company of Biologists
Date: 15-02-2011
DOI: 10.1242/DEV.064022
Publisher: Elsevier BV
Date: 11-2016
Publisher: The American Association of Immunologists
Date: 15-04-2007
DOI: 10.4049/JIMMUNOL.178.8.4764
Abstract: NK cells are important for the clearance of tumors, parasites, and virus-infected cells. Thus, factors that control NK cell numbers and function are critical for the innate immune response. A subset of NK cells express the inhibitory killer cell lectin-like receptor G1 (KLRG1). In this study, we identify that KLRG1 expression is acquired during periods of NK cell ision such as development and homeostatic proliferation. KLRG1+ NK cells are mature in phenotype, and we show for the first time that these cells have a slower in vivo turnover rate, reduced proliferative response to IL-15, and poorer homeostatic expansion potential compared with mature NK cells lacking KLRG1. Transfer into lymphopenic recipients indicate that KLRG1− NK cells are precursors of KLRG1+ NK cells and KLRG1 expression accumulates following cell ision. Furthermore, KLRG1+ NK cells represent a significantly greater proportion of NK cells in mice with enhanced NK cell numbers such as Cd45−/− mice. These data indicate that NK cells acquire KLRG1 on their surface during development, and this expression correlates with functional distinctions from other peripheral NK cells in vivo.
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1038/NI.2261
Abstract: Germinal centers require CD4⁺ follicular helper T cells (TFH cells), whose hallmark is expression of the transcriptional repressor Bcl-6, the chemokine receptor CXCR5 and interleukin 21 (IL-21). To track the development and fate of TFH cells, we generated an IL-21 reporter mouse by introducing sequence encoding green fluorescent protein (GFP) into the Il21 locus these mice had expression of IL-21–GFP in CD4⁺CXCR5⁺PD-1⁺ TFH cells. IL-21–GFP⁺ TFH cells were multifunctional helper cells that coexpressed several cytokines, including interferon-g (IFN-g), IL-2 and IL-4. TFH cells proliferated and gave rise to transferrable memory cells with plasticity, which differentiated after recall into conventional effector helper T cells and TFH cells. Thus, we demonstrated that TFH cells were not terminally differentiated but instead retained the flexibility to be recruited into other helper T cell subsets and nonlymphoid tissues.
Publisher: Rockefeller University Press
Date: 02-05-2005
DOI: 10.1084/JEM.20042294
Abstract: Engagement of receptors on the surface of natural killer (NK) cells initiates a biochemical cascade ultimately triggering cytokine production and cytotoxicity, although the interrelationship between these two outcomes is currently unclear. In this study we investigate the role of the cell surface phosphatase CD45 in NK cell development and intracellular signaling from activating receptors. Stimulation via the major histocompatibility complex I–binding receptor, Ly49D on CD45−/− primary NK cells resulted in the activation of phosphoinositide-3-kinase and normal cytotoxicity but failed to elicit a range of cytokines and chemokines. This blockage is associated with impaired phosphorylation of Syk, Vav1, JNK, and p38, which mimics data obtained using inhibitors of the src-family kinases (SFK). These data, supported by analogous findings after CD16 and NKG2D stimulation of CD45−/− primary NK cells, place CD45 upstream of SFK in NK cells after stimulation via immunoreceptor tyrosine-based activation motif-containing receptors. Thus we identify CD45 as a pivotal enzyme in eliciting a precise subset of NK cell responses.
Publisher: Rockefeller University Press
Date: 23-12-2022
DOI: 10.1084/JEM.20212333
Abstract: The generation of high-affinity antibodies in the germinal center (GC) requires interplay between GC B cells and T follicular helper cells. Rauschmeier et al. (2021. J. Exp. Med.0.1084/jem.20211406) report that Bhlhe40 restrains GC output through distinct regulatory roles in both arms of the response.
Publisher: Walter de Gruyter GmbH
Date: 1999
DOI: 10.1515/BC.1999.077
Abstract: It is generally assumed that most mammalian genes are transcribed from both alleles. Hence, the diploid state of the genome offers the advantage that a loss-of-function mutation in one allele can be compensated for by the remaining wild-type allele of the same gene. Indeed, the vast majority of human disease syndromes and engineered mutations in the mouse genome are recessive, indicating that recessiveness is the ‘default’ state. However, a minority of genes are semi-dominant, as heterozygous loss-of-function mutation in these genes leads to phenotypic abnormalities. This condition, known as haploinsufficiency, has been described for five of the nine mammalian
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.CUB.2006.01.047
Abstract: In the zebrafish embryo, primitive hematopoiesis initiates in two spatially distinct regions. Rostrally, the cells of the anterior lateral plate mesoderm (ALPM) give rise exclusively to cells of the myeloid lineage in a pu.1-dependent manner. Caudally, in the posterior lateral plate mesoderm (PLPM), the expression of gata1 defines a precursor pool that gives rise predominantly to the embryonic erythrocytes. The transcription factor scl acts upstream of both gata1 and pu.1 in these precursor pools, activating a series of conserved transcription factors that cell-autonomously specify either myeloid or erythroid fates. However, the mechanisms underlying the spatial separation of the hematopoietic precursor pools and the induction of differential gene expression within these pools are not well understood. We show here that the Bmp receptor lost-a-fin/alk8 is required for rostral pu.1 expression and myelopoiesis, identifying an early genetic event that distinguishes between the induction of anterior and posterior hematopoiesis. Introducing a constitutively active version of the Alk8 receptor led to increased pu.1 expression, but the role of alk8 was independent of the scl-dependent cell-fate pathway. Furthermore, the role of Alk8 in myelopoiesis was genetically separable from its earlier role in dorsal-ventral embryonic patterning.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.SMIM.2008.05.003
Abstract: While it has long been known that the transcription factor c-Myb is an essential regulator of hematopoiesis, its precise molecular targets have remained elusive. Cell line studies suggest that c-Myb promotes proliferation and at the same time inhibits differentiation, however the early lethality of c-Myb deficient embryos precluded analysis of its role in adult hematopoiesis. Here we review insights derived from recently developed mouse models of c-Myb deficiency that are viable as adults. These studies reveal a complex array of functions for c-Myb in multiple hematopoietic cell types that will redefine our understanding of this crucial transcription factor.
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.IMMUNI.2007.04.007
Abstract: Blimp-1 is considered an essential regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. We show here that Rag1-/- mice reconstituted with fetal liver cells homozygous for a DNA-binding-deficient mutant of Prdm1 (the gene encoding Blimp-1) lack a defined plasma-cell compartment, yet show detectable amounts of all immunoglobulin isotypes. In vitro analysis revealed that Blimp-1 is not required for the initiation of antibody secretion but is essential for subsequent high immunoglobulin production. Blimp-1-independent differentiation was blocked at a preplasmablast stage characterized by decreased Pax5 expression and the activation of plasma-cell genes. Analysis of Blimp-1-sufficient differentiation revealed a phase prior to Blimp-1 expression in which several genes normally repressed by Pax5 are re-expressed, suggesting that plasma-cell differentiation is initiated by the inhibition of Pax5 function. Our results indicate that full plasma-cell differentiation but not commitment to the plasma-cell fate requires the expression of functional Blimp-1.
Publisher: The American Association of Immunologists
Date: 10-2012
Abstract: During B cell terminal differentiation, a complex set of transcription factors interact to drive the phenotypic and functional changes leading to the development of Ab-secreting cells (ASCs). The transcription factor X-box binding protein 1 (XBP-1) is an essential part of one of the branches of the unfolded protein response (UPR). The UPR is induced when a cell has to handle large amounts of proteins, as is the case in ASCs. Although XBP-1 was initially also ascribed an indispensable function in plasma cell development, later studies of B cell-specific deletion reported a much milder consequence of XBP-1 deficiency. Our interest was to determine whether XBP-1 was integral for the differentiation of plasma cells. Using both in vitro and in vivo assays, we found efficient generation of ASCs in the absence of XBP-1. ASCs were present at normal frequencies in resting and immunized mice and displayed a pattern of surface markers typical for plasma cells. The absence of XBP-1 resulted in a reduction but not ablation of Ab secretion and the failure to develop the cellular morphology characteristic of ASCs. Thus, XBP-1 deficiency demonstrates that the gene regulatory program controlling plasma cell differentiation can proceed relatively normally in the absence of high rates of Ig secretion.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-04-2019
Abstract: The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.
Publisher: Oxford University Press (OUP)
Date: 06-10-2017
DOI: 10.1104/PP.17.00744
Publisher: Elsevier BV
Date: 06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 26-03-2022
DOI: 10.1101/2022.03.25.485728
Abstract: Despite their common use in research, monoclonal antibodies are currently not systematically sequenced. This can lead to issues with reproducibility and the occasional loss of antibodies with loss of cell lines. Hybridoma cell lines have been the primary means of generating monoclonal antibodies from immunized animals including mice, rats, rabbits and alpacas. Excluding therapeutic antibodies, few hybridoma-derived antibody sequences are known. Sanger sequencing has been “the gold standard” for antibody gene sequencing but relies on the availability of species-specific degenerate primer sets for lification of light and heavy antibody genes, in addition to lengthy and expensive cDNA preparation. Here we leveraged recent improvements in long-read Oxford Nanopore Technologies (ONT) sequencing to develop NAb-seq: a three-day, species-independent, and cost-effective workflow to characterize paired full-length immunoglobulin light and heavy chain genes from hybridoma cell lines. When compared to Sanger sequencing of two hybridoma cell lines, long-read ONT sequencing was highly accurate, reliable, and amenable to high throughput. We further show that the method is applicable to single cells, allowing efficient antibody discovery in rare populations such as memory B cells. In summary, NAb-seq promises to accelerate identification and validation of hybridoma antibodies as well as antibodies from single B cells used in research, diagnostics and therapeutics.
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2015
Abstract: The ETS family transcription factor PU.1 is essential for the development of several blood lineages, including T cells, but its function in intrathymic T-cell precursors has been poorly defined. In the thymus, high PU.1 expression persists through multiple cell isions in early stages but then falls sharply during T-cell lineage commitment. PU.1 silencing is critical for T-cell commitment, but it has remained unknown how PU.1 activities could contribute positively to T-cell development. Here we employed conditional knockout and modified antagonist PU.1 constructs to perturb PU.1 function stage-specifically in early T cells. We show that PU.1 is needed for full proliferation, restricting access to some non-T fates, and controlling the timing of T-cell developmental progression such that removal or antagonism of endogenous PU.1 allows precocious access to T-cell differentiation. Dominant-negative effects reveal that this repression by PU.1 is mediated indirectly. Genome-wide transcriptome analysis identifies novel targets of PU.1 positive and negative regulation affecting progenitor cell signaling and cell biology and indicating distinct regulatory effects on different subsets of progenitor cell transcription factors. Thus, in addition to supporting early T-cell proliferation, PU.1 regulates the timing of activation of the core T-lineage developmental program.
Publisher: Walter de Gruyter GmbH
Date: 28-02-2020
Abstract: The polycomb repressive complex 2 (PRC2) consists of three core components EZH2, SUZ12 and EED. EZH2 catalyzes the methylation of lysine 27 of histone H3, a modification associated with gene silencing. Through gene duplication higher vertebrate genomes also encode a second partially redundant methyltransferase, EZH1. Within the mammalian immune system most research has concentrated on EZH2 which is expressed predominantly in proliferating cells. EZH2 and other PRC2 components are required for hematopoietic stem cell function and lymphocyte development, at least in part by repressing cell cycle inhibitors. At later stages of immune cell differentiation, EZH2 plays essential roles in humoral and cell-mediated adaptive immunity, as well as the maintenance of immune homeostasis. EZH2 is often overactive in cancers, through both gain-of-function mutations and over-expression, an observation that has led to the development and clinical testing of specific EZH2 inhibitors. Such inhibitors may also be of use in inflammatory and autoimmune settings, as EZH2 inhibition d ens the immune response. Here, we will review the current state of understanding of the roles for EZH2, and PRC2 more generally, in the development and function of the immune system.
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2023
DOI: 10.1101/2023.05.24.542206
Abstract: The production of antibody by members of the B-cell lineage is essential for protective immunity. The clonal selection theory posits that each mature B cell has a unique immunoglobulin receptor, generated through random gene recombination, and when stimulated to differentiate into an antibody-secreting cell has the capacity to produce only a single antibody specificity. Based on this classical, “one cell one antibody” dogma, analysis of single cell RNA sequencing data of antibody-secreting cells should reveal that each cell expresses only a single form of each of the immunoglobulin heavy and light chains. However, when using GRCh38 as the genome reference, many plasma cells appear to express multiple immunoglobulin isotypes. We show that this false mapping is caused by the inaccurate immunoglobulin sequences provided by GRCh38. The newly published human genome reference T2T-CHM13, due to its more accurate sequences, avoids this false mapping caveat. In addition, further reads mapped to GRCh38 with ambiguity also settle down perfectly. These studies reveal that the sequences of the immunoglobulin genes within T2T-CHM13 are more accurate than GRCh38. Thus T2T-CHM13 is the reference genome of choice for accurate mapping and identification of the human immunoglobulin genes.
Publisher: Rockefeller University Press
Date: 13-11-2006
DOI: 10.1084/JEM.20061289
Abstract: After induction in secondary lymphoid organs, a subset of antibody-secreting cells (ASCs) homes to the bone marrow (BM) and contributes to long-term antibody production. The factors determining secondary lymphoid organ residence versus BM tropism have been unclear. Here we demonstrate that in mice treated with FTY720 or that lack sphingosine-1-phosphate (S1P) receptor-1 (S1P1) in B cells, IgG ASCs are induced and localize normally in secondary lymphoid organs but they are reduced in numbers in blood and BM. Many IgG ASCs home to BM on day 3 of the secondary response and day 3 splenic ASCs exhibit S1P responsiveness, whereas the cells remaining at day 5 are unable to respond. S1P1 mRNA abundance is higher in ASCs isolated from blood compared to spleen, whereas CXCR4 expression is lower. Blood ASCs also express higher amounts of Kruppel-like factor (KLF)2, a regulator of S1P1 gene expression. These findings establish an essential role for S1P1 in IgG plasma cell homing and they suggest that differential regulation of S1P1 expression in differentiating plasma cells may determine whether they remain in secondary lymphoid organs or home to BM.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-08-2013
Abstract: The regulated expression of transcription factors determines cell fate decisions during cell differentiation. The transcription factor PU.1 is an important determinant in the differentiation of hematopoietic progenitors to lymphocytes or myeloid cells, where high expression induces macrophage differentiation, whereas low expression leads to the development of B lymphocytes. How PU.1 expression levels are regulated during this cell fate choice, however, is not well understood. Kueh et al. (p. 670 , published online 18 July) found that in mice, reduced transcription of PU.1 led to its reduced expression in developing B lymphocytes, whereas in macrophages, PU.1 was able to accumulate stably because of a lengthening of the cell cycle. Exogenous expression of PU.1 in progenitors supported cell cycle lengthening and macrophage differentiation, and mathematical modeling suggested that such a feedback loop could maintain a slow- iding macrophage developmental state.
Publisher: Begell House
Date: 2004
DOI: 10.1615/CRITREVIMMUNOL.V24.I4.20
Abstract: The common gamma chain family of cytokine receptors plays a plethora of roles during the early development, activation, and terminal differentiation of the lymphocyte lineages. The most recently identified member of this family, the IL-21R, is expressed to varying degrees on B, T lymphocytes, and natural killer (NK) cells, whereas IL-21, is reportedly only produced by activated CD4+ T cells. In keeping with this expression pattern the IL-21:IL-21R interaction is important for the latter stages and function of all three lymphoid lineages. IL-21 is a regulator of A-cell differentiation to plasma cells as well as immunoglobulin class switching. In contrast, within the T-cell lineage, IL-21 acts as a co-stimulator of proliferation, enhances memory response, and modulates homeostasis. Within the innate immune system IL-21 has a role in the terminal differentiation of NK cells, enhancing cytotoxic function while also decreasing cellular viability. These immune maturation and stimulating functions have resulted in IL-21 being tested in a variety of models of immunity. In these contexts, IL-21 has shown very promising efficacy in a number of antitumor immune responses mediated by NK and or T lymphocytes.
Publisher: Springer Science and Business Media LLC
Date: 06-2010
DOI: 10.1038/NI0610-464
Publisher: Elsevier BV
Date: 06-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 29-01-2002
Abstract: The transgenic technique in Xenopus allows one to misexpress genes in a temporally and spatially controlled manner. However, this system suffers from two experimental limitations. First, the restriction enzyme-mediated integration procedure relies on chromosomal damage, resulting in a percentage of embryos failing to develop normally. Second, every transgenic embryo has unique sites of integration and unique transgene copy number, resulting in variable transgene expression levels and variable phenotypes. For these reasons, we have adapted the Gal4-UAS method for targeted gene expression to Xenopus . This technique relies on the generation of transgenic lines that carry “activator” or “effector” constructs. Activator lines express the yeast transcription factor, Gal4, under the control of a desired promoter, whereas effector lines contain DNA-binding motifs for Gal4-(UAS) linked to the gene of interest. We show that on intercrossing of these lines, the effector gene is transcribed in the temporal and spatial manner of the activator's promoter. Furthermore, we use the Gal4-UAS system to misexpress Xvent-2, a transcriptional target of bone morphogenetic protein 4 (BMP4) signaling during early embryogenesis. Embryos inheriting both the Gal4 activator and Xvent-2 effector transgenes display a consistent microcephalic phenotype. Finally, we exploit this system to characterize the neural and mesodermal defects obtained from early misexpression of Xvent-2. These results emphasize the potential of this system for the controlled analyses of gene function in Xenopus .
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3512977
Publisher: Cold Spring Harbor Laboratory
Date: 2008
Abstract: One critical issue for cancer biology is the nature of the cells that drive the inexorable growth of malignant tumors. Reports that only rare cell populations within human leukemias seeded leukemia in mice stimulated the now widely embraced hypothesis that only such "cancer stem cells" maintain all tumor growth. However, the mouse microenvironment might instead fail to support the dominant human tumor cell populations. Indeed, on syngeneic transplantation of mouse lymphomas and leukemias, we and other investigators have found that a substantial proportion (>10%) of their cells drive tumor growth. Thus, dominant clones rather than rare cancer stem cells appear to sustain many tumors. Another issue is the role of cell survival in tumorigenesis. Because tumor development can be promoted by the overexpression of prosurvival genes such as bcl-2, we are exploring the role of endogenous Bcl-2-like proteins in lymphomagenesis. The absence of endogenous Bcl-2 in mice expressing an Emu-myc transgene reduced mature B-cell numbers and enhanced their apoptosis, but unexpectedly, lymphoma development was undiminished or even delayed. This suggests that these tumors originate in an earlier cell type, such as the pro-B or pre-B cell, and that the nascent neoplastic clones do not require Bcl-2 but may instead be protected by a Bcl-2 relative.
Publisher: Springer Science and Business Media LLC
Date: 06-03-2011
DOI: 10.1038/NI.2006
Abstract: Regulatory T cells (T(reg) cells) are required for peripheral tolerance. Evidence indicates that T(reg) cells can adopt specialized differentiation programs in the periphery that are controlled by transcription factors usually associated with helper T cell differentiation. Here we demonstrate that expression of the transcription factor Blimp-1 defined a population of T(reg) cells that localized mainly to mucosal sites and produced IL-10. Blimp-1 was required for IL-10 production by these cells and for their tissue homeostasis. We provide evidence that the transcription factor IRF4, but not the transcription factor T-bet, was essential for Blimp-1 expression and for the differentiation of all effector T(reg) cells. Thus, our study defines a differentiation pathway that leads to the acquisition of T(reg) cell effector functions and requires both IRF4 and Blimp-1.
Publisher: Springer Science and Business Media LLC
Date: 10-1999
DOI: 10.1038/44076
Abstract: The Pax5 gene encoding the B-cell-specific activator protein (BSAP) is expressed within the haematopoietic system exclusively in the B-lymphoid lineage, where it is required in vivo for progression beyond the pro-B-cell stage. However, Pax5 is not essential for in vitro propagation of pro-B cells in the presence of interleukin-7 and stromal cells. Here we show that pro-B cells lacking Pax5 are also incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction. Pax5-/- pro-B cells are not restricted in their lineage fate, as stimulation with appropriate cytokines induces them to differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes and natural killer cells. As expected for a clonogenic haematopoietic progenitor with lymphomyeloid developmental potential, the Pax5-/- pro-B cell expresses genes of different lineage-affiliated programmes, and restoration of Pax5 activity represses this lineage-promiscuous transcription. Pax5 therefore plays an essential role in B-lineage commitment by suppressing alternative lineage choices.
Publisher: Wiley
Date: 20-03-2022
DOI: 10.1111/IMCB.12541
Abstract: The chemokine receptor CXCR3 is expressed on immune cells to co‐ordinate lymphocyte activation and migration. CXCR3 binds three chemokine ligands, CXCL9, CXCL10 and CXCL11. These ligands display distinct expression patterns and ligand signaling biases however, how each ligand functions in idually and collaboratively is incompletely understood. CXCL9 and CXCL10 are considered pro‐inflammatory chemokines during viral infection, while CXCL11 may induce a tolerizing state. The investigation of the in idual role of CXCL11 in vivo has been h ered as C57BL/6 mice carry several mutations that result in a null allele. Here, CRISPR/Cas9 was used to correct these mutations on a C57BL/6 background. It was validated that CXCL11 KI mice expressed CXCL11 protein in dendritic cells, spleen and lung. CXCL11 KI mice were largely phenotypically indistinguishable from C57BL/6 mice, both at steady‐state and during two models of viral infection. While CXCL11 expression did not modify acute antiviral responses, this study provides a new tool to understand the role of CXCL11 in other experimental settings.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2014
DOI: 10.1038/NCOMMS5539
Abstract: The cytokine IL-15 is required for natural killer (NK) cell homeostasis however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.
Publisher: Informa UK Limited
Date: 08-2007
DOI: 10.1128/MCB.00802-07
Publisher: American Society of Hematology
Date: 29-05-2014
DOI: 10.1182/BLOOD-2014-03-561456
Abstract: Loss of Id2 in T cells results in overexpression of IL-10 during influenza infection and GVHD and protects against GVHD immunopathology. Id2 represses the direct E2A-mediated activation of the Il10 locus in effector T cells.
Publisher: American Society of Hematology
Date: 21-02-2019
Publisher: Springer Science and Business Media LLC
Date: 17-08-2022
DOI: 10.1038/S41586-022-05105-1
Abstract: CD8 + T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion 1,2 —is maintained by precursors of exhausted T (T PEX ) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1 − exhausted effector T cells 3–6 . Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L + T PEX cells. The transcription factor MYB is not only essential for the development of CD62L + T PEX cells and maintenance of the antiviral CD8 + T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L + T PEX cells and depends on MYB. Our findings identify CD62L + T PEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.
Publisher: Rockefeller University Press
Date: 10-2012
DOI: 10.1084/JEM.20112744
Abstract: Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing in idual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell–independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.
Publisher: Frontiers Media SA
Date: 11-06-2018
Publisher: Springer Science and Business Media LLC
Date: 06-02-2015
DOI: 10.1038/LEU.2015.27
Publisher: Springer Science and Business Media LLC
Date: 31-10-2022
Publisher: Informa UK Limited
Date: 13-08-2022
DOI: 10.1080/19420862.2022.2106621
Abstract: Despite their common use in research, monoclonal antibodies are currently not systematically sequenced. This can lead to issues with reproducibility and the occasional loss of antibodies with loss of cell lines. Hybridoma cell lines have been the primary means of generating monoclonal antibodies from immunized animals, including mice, rats, rabbits, and alpacas. Excluding therapeutic antibodies, few hybridoma-derived antibody sequences are known. Sanger sequencing has been "the gold standard" for antibody gene sequencing, but this method relies on the availability of species-specific degenerate primer sets for lification of light and heavy antibody genes and it requires lengthy and expensive cDNA preparation. Here, we leveraged recent improvements in long-read Oxford Nanopore Technologies (ONT) sequencing to develop Nanopore Antibody sequencing (NAb-seq): a three-day, species-independent, and cost-effective workflow to characterize paired full-length immunoglobulin light- and heavy-chain genes from hybridoma cell lines. When compared to Sanger sequencing of two hybridoma cell lines, long-read ONT sequencing was highly accurate, reliable, and amenable to high throughput. We further show that the method is applicable to single cells, allowing efficient antibody discovery in rare populations such as memory B cells. In summary, NAb-seq promises to accelerate identification and validation of hybridoma antibodies as well as antibodies from single B cells used in research, diagnostics, and therapeutics.
Publisher: Wiley
Date: 2008
DOI: 10.1002/BIES.20725
Abstract: The transcription factor Pax5 is essential for the initial commitment of hematopoietic progenitors to the B cell lineage. Recently, our understanding of the lineage commitment process has been extended with the finding that Pax5 is also continuously required throughout B cell development to reinforce commitment, as inactivation of Pax5 in mature B cells results in their de-differentiation to a progenitor stage that is capable of multi-lineage potential. The reliance of B cell identity on a single gene is not without its problems as the loss of Pax5 results in B cell malignancies in mouse models and mutation in human PAX5 is the most-common genetic lesion in acute lymphoblastic leukemia.
Publisher: Springer Science and Business Media LLC
Date: 10-1999
DOI: 10.1038/44164
Abstract: The mechanisms controlling the commitment of haematopoietic progenitors to the B-lymphoid lineage are poorly understood. The observations that mice deficient in E2A and EBF lack B-lineage cells have implicated these two transcription factors in the commitment process. Moreover, the expression of genes encoding components of the rearrangement machinery (RAG1, RAG2, TdT) or pre-B-cell receptor (lambda5, VpreB, Igalpha, Igbeta) has been considered to indicate B-lineage commitment. All these genes including E2A and EBF are expressed in pro-B cells lacking the transcription factor Pax5. Here we show that cloned Pax5-deficient pro-B cells transferred into RAG2-deficient mice provide long-term reconstitution of the thymus and give rise to mature T cells expressing alpha/beta-T-cell receptors. The bone marrow of these mice contains a population of cells of Pax5-/- origin with the same phenotype as the donor pro-B cells. When transferred into secondary recipients, these pro-B cells again home to the bone marrow and reconstitute the thymus. Hence, B-lineage commitment is determined neither by immunoglobulin DJ rearrangement nor by the expression of E2A, EBF, lambda5, VpreB, Igalpha and Igbeta. Instead, our data implicate Pax5 in the control of B-lineage commitment.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-11-2010
Abstract: The humoral immune response, which comprises antibodies secreted by B lymphocytes, is critical for protection against pathogens. In response to infection, B lymphocytes proliferate and differentiate into antibody-producing effector cells. After an infection clears, a small number of cells persist as memory B cells however, the survival signals that regulate effector and memory B lymphocyte generation are not well understood. To probe this question, Vikstrom et al. (p. 1095 , published online 7 October) deleted prosurvival genes in activated, antigen-specific B cells during a T lymphocyte–dependent immune response in mice. They found that a specific programmed cell death inhibitor, known as Mcl1, was required for the formation of germinal-center B cells (an effector cell population) and memory B cells but not for their maintenance. Dysregulation of the B cell responses mediated by Mcl1 may be a trigger for lymphomagenesis.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2019
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.IMMUNI.2009.06.021
Abstract: In response to viral infection, naive CD8(+) T cells proliferate and differentiate into cytotoxic and cytokine-producing effector cells. Here we showed that the transcription factor Blimp-1, a crucial regulator of plasma cell differentiation, was required for CD8(+) T cells to differentiate into functional killer T cells in response to influenza virus. Blimp-1 was not essential for the generation of memory T cells but was crucial for their efficient recall response upon reinfection. Antigen-specific Blimp-1-deficient CD8(+) T cells failed to appropriately regulate the transcriptional program essential for killer T cell responses and showed impaired migration to the site of infection. This study identifies Blimp-1 as a master regulator of the terminal differentiation of CD8(+) effector T cells and uncovers a conservation of the pathways that regulate the terminal differentiation of T and B cells.
Publisher: The American Association of Immunologists
Date: 15-08-2014
Abstract: The IFN regulatory factor family member 8 (IRF8) regulates differentiation of lymphoid and myeloid lineage cells by promoting or suppressing lineage-specific genes. How IRF8 promotes hematopoietic progenitors to commit to one lineage while preventing the development of alternative lineages is not known. In this study, we report an IRF8–EGFP fusion protein reporter mouse that revealed previously unrecognized patterns of IRF8 expression. Differentiation of hematopoietic stem cells into oligopotent progenitors is associated with progressive increases in IRF8-EGFP expression. However, significant induction of IRF8-EGFP is found in granulocyte–myeloid progenitors and the common lymphoid progenitors but not the megakaryocytic–erythroid progenitors. Surprisingly, IRF8-EGFP identifies three subsets of the seemingly homogeneous granulocyte–myeloid progenitors with an intermediate level of expression of EGFP defining bipotent progenitors that differentiation into either EGFPhi monocytic progenitors or EGFPlo granulocytic progenitors. Also surprisingly, IRF8-EGFP revealed a highly heterogeneous pre–pro-B population with a fluorescence intensity ranging from background to 4 orders above background. Interestingly, IRF8–EGFP readily distinguishes true B cell committed (EGFPint) from those that are noncommitted. Moreover, dendritic cell progenitors expressed extremely high levels of IRF8-EGFP. Taken together, the IRF8-EGFP reporter revealed previously unrecognized subsets with distinct developmental potentials in phenotypically well-defined oligopotent progenitors, providing new insights into the dynamic heterogeneity of developing hematopoietic progenitors.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
DOI: 10.1038/S41467-021-22973-9
Abstract: Neutrophils are implicated in multiple homeostatic and pathological processes, but whether functional ersity requires discrete neutrophil subsets is not known. Here, we apply single-cell RNA sequencing to neutrophils from normal and inflamed mouse tissues. Whereas conventional clustering yields multiple alternative organizational structures, diffusion mapping plus RNA velocity discloses a single developmental spectrum, ordered chronologically. Termed here neutrotime, this spectrum extends from immature pre-neutrophils, largely in bone marrow, to mature neutrophils predominantly in blood and spleen. The sharpest increments in neutrotime occur during the transitions from pre-neutrophils to immature neutrophils and from mature marrow neutrophils to those in blood. Human neutrophils exhibit a similar transcriptomic pattern. Neutrophils migrating into inflamed mouse lung, peritoneum and joint maintain the core mature neutrotime signature together with new transcriptional activity that varies with site and stimulus. Together, these data identify a single developmental spectrum as the dominant organizational theme of neutrophil heterogeneity.
Publisher: American Society of Hematology
Date: 12-2004
DOI: 10.1182/BLOOD-2004-06-2234
Abstract: In most myeloid leukemias induced in mice by γ-radiation, one copy of chromosome 2 has suffered a deletion. To search for a potential tumor suppressor gene in that region, we have delineated the deletions in a panel of these tumors. A commonly deleted region of 2 megabase pairs (Mbp) includes the gene encoding the PU.1 transcription factor, a powerful inducer of granulocytic/monocytic differentiation. Significantly, in 87% of these tumors the remaining PU.1 allele exhibited point mutations in the PU.1 DNA binding domain. Surprisingly, 86% of these mutations altered a single CpG, implicating deamination of deoxycytidine, a common mutational mechanism, as the origin of this lesion. The “hot spot” resides in the codon for a contact residue essential for DNA binding by PU.1. In keeping with a tumor suppressor role for PU.1, enforced expression of wild-type PU.1 in the promyelocytic leukemia cells inhibited their clonogenic growth, induced monocytic differentiation, and elicited apoptosis. The mutant PU.1 found in tumors retained only minimal growth suppressive function. The results suggest that PU.1 normally suppresses development of myeloid leukemia by promoting differentiation and that the combination of gene deletion and a point mutation that impairs its ability to bind DNA is particularly leukemogenic.
Publisher: Impact Journals, LLC
Date: 28-06-2015
Publisher: Elsevier BV
Date: 04-2000
DOI: 10.1016/S0952-7915(99)00065-5
Abstract: The mechanisms controlling the commitment of hematopoietic progenitor cells to the lymphoid lineages are still mostly unknown. Recent findings indicate that the earliest phase of B cell development may proceed in two steps. At the onset of B-lymphopoiesis, the transcription factors E2A and EBF coordinately activate the B-cell-specific gene expression program. Subsequently, Pax5 appears to repress the promiscuous transcription of lineage-inappropriate genes and thus commits progenitor cells to the B-lymphoid pathway by suppressing alternative cell fates. B-lineage commitment by Pax5 seems to occur in a stochastic manner in the bone marrow, as indicated by the random activation of only one of the two Pax5 alleles in early pro-B cells. In contrast, loss- and gain-of-function analyses have implicated the Notch1 receptor in the specification of the T cell fate, which may thus be controlled by instructive signals in the thymus.
Publisher: American Society of Hematology
Date: 15-09-2005
DOI: 10.1182/BLOOD-2005-01-0283
Abstract: An abundance of research has entrenched the view that the Ets domain containing transcription factor PU.1 is fundamental to the development and function of B lymphocytes. In this study, we have made use of a conditional PU.1 allele to test this notion. Complete deletion of PU.1 resulted in the loss of B cells and all other lineage-positive cells in the fetal liver and death between E18.5 and birth however, specific deletion of PU.1 in the B lineage had no effect on B-cell development. Furthermore, deletion of PU.1 in B cells did not compromise their ability to establish and maintain an immune response. An increased level of apoptosis was observed in vitro upon B-cell receptor (BCR) cross-linking however, this was partially rescued by interleukin-4 (IL-4). These findings suggest that PU.1 is not essential for the development of functional B lymphocytes beyond the pre-B stage. (Blood. 2005 :2083-2090)
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.IMMUNI.2015.07.015
Abstract: Asthma is a T helper 2 (Th2)-cell-mediated disease however, recent findings implicate Th17 and innate lymphoid cells also in regulating airway inflammation. Herein, we have demonstrated profound interleukin-21 (IL-21) production after house dust mite (HDM)-driven asthma by using T cell receptor (TCR) transgenic mice reactive to Dermatophagoides pteronyssinus 1 and an IL-21GFP reporter mouse. IL-21-producing cells in the mediastinal lymph node (mLN) bore characteristics of T follicular helper (Tfh) cells, whereas IL-21(+) cells in the lung did not express CXCR5 (a chemokine receptor expressed by Tfh cells) and were distinct from effector Th2 or Th17 cells. Il21r(-/-) mice developed reduced type 2 responses and the IL-21 receptor (IL-21R) enhanced Th2 cell function in a cell-intrinsic manner. Finally, administration of recombinant IL-21 and IL-25 synergistically promoted airway eosinophilia primarily via effects on CD4(+) lymphocytes. This highlights an important Th2-cell- lifying function of IL-21-producing CD4(+) T cells in allergic airway inflammation.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2006
DOI: 10.1038/NI1321
Abstract: T cell homeostasis is crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatory T cells or an inability to shut down immune responses can lead to inflammation and autoimmune pathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of terminal B cell differentiation, was expressed in a subset of antigen-experienced CD4(+) and CD8(+) T cells. Mice reconstituted with fetal liver stem cells expressing a mutant Blimp-1 lacking the DNA-binding domain developed a lethal multiorgan inflammatory disease caused by an accumulation of effector and memory T cells. These data identify Blimp-1 as an essential regulator of T cell homeostasis and suggest that Blimp-1 regulates both B cell and T cell differentiation.
Publisher: The American Association of Immunologists
Date: 04-2014
Abstract: In response to antigenic stimulation, mature B cells interact with follicular helper T cells in specialized structures called germinal centers (GCs), which leads to the development of memory B cells and Ab-secreting plasma cells. The transcription factor IFN regulatory factor 4 (IRF4) is essential for the formation of follicular helper T cells and thus GCs, although whether IRF4 plays a distinct role in GC B cells remains contentious. RNAseq analysis on ex vivo-derived mouse B cell populations showed that Irf4 was lowly expressed in naive B cells, highly expressed in plasma cells, but absent from GC B cells. In this study, we used conditional deletion of Irf4 in mature B cells as well as wild-type and Irf4-deficient mixed bone marrow chimeric mice to investigate how and where IRF4 plays its essential role in GC formation. Strikingly, GC formation was severely impaired in mice in which Irf4 was conditionally deleted in mature B cells, after immunization with protein Ags or infection with Leishmania major. This effect was evident as early as day 5 following immunization, before the development of GCs, indicating that Irf4 was required for the development of early GC B cells. This defect was B cell intrinsic because Irf4-deficient B cells in chimeric mice failed to participate in the GC in response to L. major or influenza virus infection. Taken together, these data demonstrate a B cell–intrinsic requirement for IRF4 for not only the development of Ab secreting plasma cells but also for GC formation.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.COI.2007.01.003
Abstract: B lymphocyte induced maturation protein 1 (Blimp-1) has long been considered a master regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. Gene-targeting experiments have now demonstrated that quantitative changes in Blimp-1 expression define plasma cell ontogeny--a process that requires the continual function of Blimp-1. Recently, new roles for Blimp-1 have been revealed, as a suppressor of diffuse large B cell lymphoma and as a key regulator of T-cell differentiation. Blimp-1 is expressed in differentiated effector T cells and controls their homeostasis. These new findings suggest that Blimp-1 has a conserved function in the final differentiation of both the cellular and the humoral arm of the adaptive immune response.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Cold Spring Harbor Laboratory
Date: 05-2001
DOI: 10.1101/GAD.191301
Abstract: Signal transduction through the FGF receptor is essential for the specification of the vertebrate body plan. Blocking the FGF pathway in early Xenopus embryos inhibits mesoderm induction and results in truncation of the anterior–posterior axis. The Drosophila gene sprouty encodes an antagonist of FGF signaling, which is transcriptionally induced by the pathway, but whose molecular functions are poorly characterized. We have cloned Xenopus sprouty2 and show that it is expressed in a similar pattern to known FGFs and is dependent on the FGF/Ras/MAPK pathway for its expression. Overexpression of Xsprouty2 in both embryos and explant assays results in the inhibition of the cell movements of convergent extension. Although blocking FGF/Ras/MAPK signaling leads to an inhibition of mesodermal gene expression, these markers are unaffected by Xsprouty2, indicating that mesoderm induction and patterning occurs normally in these embryos. Finally, using Xenopus oocytes we show that Xsprouty2 is an intracellular antagonist of FGF-dependent calcium signaling. These results provide evidence for at least two distinct FGF-dependent signal transduction pathways: a Sprouty-insensitive Ras/MAPK pathway required for the transcription of most mesodermal genes, and a Sprouty-sensitive pathway required for coordination of cellular morphogenesis.
Publisher: The American Association of Immunologists
Date: 02-2008
DOI: 10.4049/JIMMUNOL.180.3.1719
Abstract: The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression while simultaneously activating the B cell gene expression program. In this study we have performed a global gene expression screen of wild-type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B lymphopoiesis. These studies have identified 109 Pax5 targets comprising 61% activated and 39% repressed genes. Interestingly, Pax5 directly regulates the genes encoding a number of transcription factors that are required at the pre-B cell stage of differentiation, including Irf8, Spib, and Ikzf3 (Aiolos), suggesting that a key function of Pax5 is to activate secondary transcription factors that further reinforce the B cell program. Pax5 is also required for the expression of many genes known to be involved in adhesion and signaling, indicating that Pax5 modulates the homing and or migration properties of B cell progenitors. Finally, Pax5 also represses a cohort of genes that are involved in multiple biological processes, many of which are not typically associated with B cells. These include the repression of the adhesion molecule Embigin, which is expressed in bone marrow progenitors, T cells, and myeloid cells but is specifically repressed by Pax5 in B cells.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2016
DOI: 10.1038/NCOMMS13600
Abstract: Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG + counterparts do not. Antigen boost modifies the gene expression profile of IgM + plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.
Publisher: Informa UK Limited
Date: 2001
DOI: 10.3109/08830180109056723
Abstract: Despite being one of the most intensively studied cell types, the molecular basis of B cell specification is largely unknown. The Pax5 gene encoding the transcription factor BSAP is required for progression of B-lymphopoiesis beyond the pro-B cell stage. Pax5-deficient pro-B cells are, however, not yet committed to the B-lymphoid lineage, but instead have a broad lymphomyeloid developmental potential. Pax5 appears to mediate B-lineage commitment by repressing the transcription of non-B-lymphoid genes and by simultaneously activating the expression of B-lineage-specific genes. Pax5 thus functions both as a transcriptional repressor and activator, depending on its interactions with corepressors of the Groucho protein family or with positive regulators such as the TATA-binding protein. Once committed to the B-lineage, B cells require Pax5 function to maintain their B-lymphoid identity throughout B cell development.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.STEM.2019.07.001
Abstract: Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1994
DOI: 10.1097/00001756-199408150-00034
Abstract: RNA editing in rat brain has been found to control a determinant of cation flow in alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA)-gated channels. Here we provide the first evidence that this RNA editing phenomenon occurs in human brain and is differentially regulated. Sequence analysis of human genomic DNA revealed a Q codon (CAG) in the putative channel-forming segment of human GluR-2, whereas in the majority of cDNA clones an R codon (CGG) was found. Examination of editing in various brain tissues revealed differences in the efficiency of this process. The hippoc us, cerebellum and temporal cortex harbour 100% edited GluR-2, whereas only 72% of substantia nigra, 89% of corpus striatum and 96% of fetal cDNAs have been found to be edited. This new discovery of differential efficiency of RNA editing has important implications in AMPA receptor channel-mediated calcium influx. AMPA receptors are thought to mediate the majority of the fast excitatory synaptic neurotransmission the RNA editing process may therefore play a critical role in normal brain function and development. Dysfunction of this RNA editing process may have neuropathological consequences and could be related to certain neurodegenerative diseases.
Publisher: American Society of Hematology
Date: 27-05-2021
Abstract: OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell–specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by chromatin immunoprecipitation-sequencing that OBF1 extensively colocalizes with OCT1 and OCT2. We found that these factors also often colocalize with transcription factors of the ETS family. Furthermore, we showed that OBF1, OCT2, and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation in mouse and human GC B cells. Short hairpin RNA knockdown experiments demonstrated that OCT1, OCT2, and OBF1 regulate each other and are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance, such as BCL6, are downregulated, whereas genes related to exit from the GC program, such as IRF4, are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived lymphoma cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls an essential regulatory node in GC differentiation.
Publisher: Wiley
Date: 08-2017
Abstract: Being the sole source of antibody, plasmablasts and plasma cells are essential for protective immunity. Due to their relative rarity, heterogeneity and the loss of many canonical B-cell markers, antibody-secreting cells (ASCs) have often been problematic to identify and further characterize. In the mouse, the combination of the expression of CD138 and BLIMP-1, has led to many insights into ASC biology, although this approach requires the use of a GFP reporter strain. In the current issue of the European Journal of Immunology, two independent studies by Wilmore et al. and Pracht et al. provide alternative approaches to identify all murine ASCs using antibodies against the cell surface proteins, Sca-1 and TACI, respectively. Here we will discuss the advantages of these new approaches to identify ASCs in the context of our emerging knowledge of the cell surface phenotype and gene expression program of various ASC subsets in the murine and human systems.
Publisher: Elsevier BV
Date: 08-2007
Publisher: Wiley
Date: 03-06-2018
DOI: 10.1111/IMCB.12163
Abstract: The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class-I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2-deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2-deficient lymphocytes show impaired degradation of key BH3-only proteins, resulting in elevated levels of pro-apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer.
Publisher: eLife Sciences Publications, Ltd
Date: 23-12-2015
DOI: 10.7554/ELIFE.10592
Abstract: TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2015
DOI: 10.1038/NI.3154
Abstract: When B cells encounter an antigen, they alter their physiological state and anatomical localization and initiate a differentiation process that ultimately produces antibody-secreting cells (ASCs). We have defined the transcriptomes of many mature B cell populations and stages of plasma cell differentiation in mice. We provide a molecular signature of ASCs that highlights the stark transcriptional ide between B cells and plasma cells and enables the demarcation of ASCs on the basis of location and maturity. Changes in gene expression correlated with cell- ision history and the acquisition of permissive histone modifications, and they included many regulators that had not been previously implicated in B cell differentiation. These findings both highlight and expand the core program that guides B cell terminal differentiation and the production of antibodies.
Publisher: Elsevier BV
Date: 10-1994
DOI: 10.1016/0167-4781(94)90090-6
Abstract: Several cDNA clones encoding the human glutamate receptor subunit GluR3 flip and flop isoforms, were isolated from human hippoc us and fetal brain libraries. DNA sequence analysis revealed overlapping clones permitting the reconstruction of full-length GluR3-flip and GluR3-flop cDNAs. The GluR3 cDNAs demonstrated an 94.1-94.7% nucleotide (nt) identity with the corresponding rat cDNAs. The nt sequence of the GluR3 cDNAs would encode 894 amino acid proteins that have a 99.4% identity with the rat GluR3 isoforms. The human GluR3 cDNAs predict an additional 6 amino acid in the N-terminal signal peptide as compared to the rat GluR3.
Publisher: American Society for Clinical Investigation
Date: 16-05-2019
Publisher: Springer Science and Business Media LLC
Date: 04-11-2020
Publisher: Oxford University Press (OUP)
Date: 06-03-2014
Publisher: Elsevier BV
Date: 03-2007
Abstract: The transcription factor PU.1 is an essential regulator of haemopoiesis and a suppressor of myeloid leukaemia. PU.1 displays a complex expression pattern characterized by high expression in myeloid cells and low amounts in lymphoid cells. Based on this transcriptional profile, and the analysis of cell lines and mice expressing altered levels of PU.1, a model has been proposed where the concentration of PU.1 determines cell fate, whereas the graded reduction, but not absence, of PU.1 facilitates leukaemogenesis. The recent reports of mouse strains that enable the accurate determination of PU.1 expression and the conditional inactivation of PU.1 in adult haemopoiesis have led us to re-examine our understanding of the complex functions of PU.1. Here, we will discuss the data that, we believe, argue against the dosage-sensitive model of PU.1-mediated lineage commitment and leukaemogenesis.
Publisher: Springer Science and Business Media LLC
Date: 12-2007
DOI: 10.1038/NRI2204
Abstract: B-lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor, and its importance in controlling the terminal differentiation of antibody-secreting cells (ASCs) is well established. However, as we discuss in this Progress article, it has now become evident that the ASC programme consists of a discrete BLIMP1-independent initiation phase, followed by a second step in which BLIMP1 is absolutely required for the differentiation of fully mature ASCs. In addition, an important role for BLIMP1 in maintaining the homeostasis of effector T cells is emerging, suggesting intriguing parallels between the control of effector-cell fates in both B and T cells.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
DOI: 10.1038/NCOMMS14911
Abstract: In response to infection and injury, the neutrophil population rapidly expands and then quickly re-establishes the basal state when inflammation resolves. The exact pathways governing neutrophil/macrophage lineage outputs from a common granulocyte-macrophage progenitor are still not completely understood. From a forward genetic screen in zebrafish, we identify the transcriptional repressor, ZBTB11, as critical for basal and emergency granulopoiesis. ZBTB11 sits in a pathway directly downstream of master myeloid regulators including PU.1, and TP53 is one direct ZBTB11 transcriptional target. TP53 repression is dependent on ZBTB11 cys116, which is a functionally critical, metal ion-coordinating residue within a novel viral integrase-like zinc finger domain. To our knowledge, this is the first description of a function for this domain in a cellular protein. We demonstrate that the PU.1–ZBTB11–TP53 pathway is conserved from fish to mammals. Finally, Zbtb11 mutant rescue experiments point to a ZBTB11-regulated TP53 requirement in development of other organs.
Publisher: eLife Sciences Publications, Ltd
Date: 27-06-2017
DOI: 10.7554/ELIFE.29849
Publisher: Springer Science and Business Media LLC
Date: 22-09-2013
DOI: 10.1038/NI.2710
Abstract: During immune responses, T cells are subject to clonal competition, which leads to the predominant expansion of high-affinity clones however, there is little understanding of how this process is controlled. We found here that the transcription factor IRF4 was induced in a manner dependent on affinity for the T cell antigen receptor (TCR) and acted as a dose-dependent regulator of the metabolic function of activated T cells. IRF4 regulated the expression of key molecules required for the aerobic glycolysis of effector T cells and was essential for the clonal expansion and maintenance of effector function of antigen-specific CD8(+) T cells. Thus, IRF4 is an indispensable molecular 'rheostat' that 'translates' TCR affinity into the appropriate transcriptional programs that link metabolic function with the clonal selection and effector differentiation of T cells.
Publisher: Wiley
Date: 03-05-2016
DOI: 10.1038/ICB.2016.33
Publisher: Public Library of Science (PLoS)
Date: 17-03-2014
Publisher: Springer Science and Business Media LLC
Date: 02-05-2010
DOI: 10.1038/NI.1867
Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2014
Abstract: Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.
Publisher: Public Library of Science (PLoS)
Date: 14-07-2011
Publisher: Elsevier BV
Date: 10-2016
Publisher: Research Square Platform LLC
Date: 02-11-2022
DOI: 10.21203/RS.3.RS-2196744/V1
Abstract: Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological maligancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis was unknown. Here we used conditional gene inactivation to reveal that Ikaros is required for normal NK cell development. Ikzf1-null NK cells had impaired IL-15 signaling, manifesting in reduced proliferation and enhanced apoptosis. Cish and Socs2, known negative regulators of IL-15 signaling are increased in Ikzf1-null NK cells and are direct targets of Ikaros-mediated repression. Ikzf1-null NK cells have extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes as well as a compensatory increase in Ikaros-family members, Ikzf2 and Ikzf3. Deletion of both Ikzf1 and Ikzf3 in NK cells further reduced AP-1 gene expression culminating in a complete loss of peripheral NK cells in mice. Inactivation of Ikaros-family members in human NK cells also impaired their fitness and function, while genetic screens revealed a co-dependency on IKZF1 and in idual AP-1 genes in hematopoietic cell survival, suggesting that IMiDs induce apoptosis of malignant IKZF1/3-dependent cells by ablating AP-1 transcriptional activity. Collectively we show the Ikaros-family are novel regulators of cytokine responsiveness and essential for promoting AP-1 transcriptional activity required for NK cell development.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2016
DOI: 10.1038/LEU.2016.27
Publisher: Rockefeller University Press
Date: 17-08-1998
Abstract: The formation of the pre-B cell receptor (BCR) corresponds to an important checkpoint in B cell development that selects pro-B (pre-BI) cells expressing a functionally rearranged immunoglobulin μ (Igμ) heavy chain protein to undergo the transition to the pre-B (pre-BII) cell stage. The pre-BCR contains, in addition to Igμ, the surrogate light chains λ5 and VpreB and the signal transducing proteins Igα and Igβ. The absence of one of these pre-BCR components is known to arrest B cell development at the pre-BI cell stage. Disruption of the Pax5 gene, which codes for the B cell–specific activator protein (BSAP), also blocks adult B lymphopoiesis at the pre-BI cell stage. Moreover, expression of the mb-1 (Igα) gene and VH-to-DHJH recombination at the IgH locus are reduced in Pax5-deficient B lymphocytes ∼10- and ∼50-fold, respectively. Here we demonstrate that complementation of these deficiencies in pre-BCR components by expression of functionally rearranged Igμ and chimeric Igμ-Igβ transgenes fails to advance B cell development to the pre-BII cell stage in Pax5 (−/−) mice in contrast to RAG2 (−/−) mice. Furthermore, the pre-BCR is stably expressed on cultured pre-BI cells from Igμ transgenic, Pax5-deficient bone marrow, but is unable to elicit its normal signaling responses. In addition, the early developmental block is unlikely to be caused by the absence of a survival signal, as it could not be rescued by expression of a bcl2 transgene in Pax5-deficient pre-BI cells. Together, these data demonstrate that the absence of Pax5 arrests adult B lymphopoiesis at an early developmental stage that is unresponsive to pre-BCR signaling.
Publisher: Rockefeller University Press
Date: 06-10-2014
DOI: 10.1084/JEM.20140425
Abstract: Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell–promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1–IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration-dependent competition between these factors controls B cell terminal differentiation.
Publisher: Rockefeller University Press
Date: 09-10-2006
DOI: 10.1084/JEM.20061254
Abstract: A hallmark of T cell–dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this “quality control” over plasma cell differentiation is likely critical for establishing effective humoral immunity.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2015
Publisher: Springer Science and Business Media LLC
Date: 27-11-2012
DOI: 10.1038/NI.2166
Abstract: Lipid antigens trigger help from natural killer T cells (NKT cells) for B cells, and direct conjugation of lipid agonists to antigen profoundly augments antibody responses. Here we show that in vivo, NKT cells engaged in stable and prolonged cognate interactions with B cells and induced the formation of early germinal centers. Mouse and human NKT cells formed CXCR5(+)PD-1(hi) follicular helper NKT cells (NKT(FH) cells), and this process required expression of the transcriptional repressor Bcl-6, signaling via the coreceptor CD28 and interaction with B cells. NKT(FH) cells provided direct cognate help to antigen-specific B cells that was dependent on interleukin 21 (IL-21). Unlike T cell-dependent germinal centers, those driven by NKT(FH) cells did not generate long-lived plasma cells. Our results demonstrate the existence of a Bcl-6-dependent subset of NKT cells specialized in providing help to B cells.
Publisher: The Company of Biologists
Date: 15-12-2007
DOI: 10.1242/DEV.012047
Abstract: The zinc-finger transcriptional repressor Blimp1 (Prdm1) controls gene expression patterns during differentiation of B lymphocytes and regulates epigenetic changes required for specification of primordial germ cells. Blimp1 is dynamically expressed at erse tissue sites in the developing mouse embryo, but its functional role remains unknown because Blimp1 mutant embryos arrest at E10.5 due to placental insufficiency. To explore Blimp1 activities at later stages in the embryo proper,here we used a conditional inactivation strategy. A Blimp1-Cretransgenic strain was also exploited to generate a fate map of Blimp1-expressing cells. Blimp1 plays essential roles in multipotent progenitor cell populations in the posterior forelimb, caudal pharyngeal arches, secondary heart field and sensory vibrissae and maintains key signalling centres at these erse tissues sites. Interestingly, embryos carrying a hypomorphic Blimp1gfp reporter allele survive to late gestation and exhibit similar, but less severe developmental abnormalities, whereas transheterozygous Blimp1gfp/-embryos with further reduced expression levels, display exacerbated defects. Collectively, the present experiments demonstrate that Blimp1requirements in erse cell types are exquisitely dose dependent.
Publisher: American Society for Microbiology
Date: 07-2011
DOI: 10.1128/JVI.00202-11
Abstract: Immunoglobulin in cerebral spinal fluid and antibody secreting cells (ASC) within the central nervous system (CNS) parenchyma are common hallmarks of microbial infections and autoimmune disorders. However, the signals directing ASC migration into the inflamed CNS are poorly characterized. This study demonstrates that CXCR3 mediates CNS accumulation of ASC during neurotropic coronavirus-induced encephalomyelitis. Expansion of CXCR3-expressing ASC in draining lymph nodes prior to accumulation within the CNS was consistent with their recruitment by sustained expression of CXCR3 ligands during viral persistence. Both total and virus-specific ASC were reduced greater than 80% in the CNS of infected CXCR3 −/− mice. Similar T cell CNS recruitment and local T cell-dependent antiviral activity further indicated that the ASC migration defect was T cell independent. Furthermore, in contrast to the reduction of ASC in the CNS, neither virus-specific ASC trafficking to bone marrow nor antiviral serum antibody was reduced relative to levels in control mice. Impaired ASC recruitment into the CNS of infected CXCR3 −/− mice coincided with elevated levels of persisting viral RNA, sustained infectious virus, increased clinical disease, and mortality. These results demonstrate that CXCR3 ligands are indispensable for recruitment of activated ASC into the inflamed CNS and highlight their local protective role during persistent infection.
Location: Australia
Start Date: 2019
End Date: 2022
Funder: Leukemia and Lymphoma Society
View Funded ActivityStart Date: 2020
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2021
End Date: 2024
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2011
End Date: 12-2014
Amount: $919,832.00
Funder: Australian Research Council
View Funded Activity