ORCID Profile
0000-0002-9660-9587
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
University of Queensland
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Immunology | Cellular Immunology | Infectious Agents | Cellular immunology | Animal Physiology - Systems | Innate immunity | Immunology not elsewhere classified | Biochemistry and Cell Biology | Cellular Immunology | Physiology | Virology | Innate Immunity | Immunology not elsewhere classified | Immunology | Biological Sciences not elsewhere classified | Cell Development, Proliferation and Death | Systems Biology
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Infectious Diseases | Immune system and allergy | Infectious diseases | Expanding Knowledge in the Medical and Health Sciences | Immune System and Allergy |
Related Links
Publications
Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival
Publisher: Rockefeller University Press
Date: 05-01-2017
DOI: 10.1084/JEM.20160869
Abstract: Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)–induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK cells.
Absence of a functional defect in CD8+ T cells during primary murine gammaherpesvirus-68 infection of I-Ab−/− mice
Publisher: Microbiology Society
Date: 02-2003
Abstract: The murine gammaherpesvirus-68 kills I-A(b-/-) mice despite the presence of virus-specific CD8+ cytotoxic T lymphocytes (CTL). This has raised the possibility that these CTL are functionally abnormal. Here, no difference was observed between I-A(b-/-) mice and I-A(b+/+) controls in virus-specific CTL function, T cell receptor usage, or surface phenotype. Thus CTL immunity was independent of CD4+ T cells in a chronic herpesvirus infection, but was still inadequate to control virus replication.
Transfer of antigen between migrating and lymph node-resident DCs in peripheral T-cell tolerance and immunity
Publisher: Elsevier BV
Date: 12-2004
Abstract: Dendritic cells (DCs) consist of a heterogeneous collection of subsets, many with unique phenotypic and functional characteristics. Although certain subsets migrate from peripheral non-lymphoid tissues, there is evidence that antigen presentation can extend to DCs that permanently reside within the lymph node. This Opinion describes this finding in the context of antigen transfer between migrating and lymphoid-resident DCs in cases of T-cell priming and tolerance induction.
Transcriptional Regulation of Dendritic Cell Diversity
Publisher: Frontiers Media SA
Date: 2012
Characterization of Blimp-1 function in effector regulatory T cells
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JAUT.2018.04.003
Abstract: Regulatory T (T
Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces [version 1; peer review: 3 approved]
Publisher: F1000 Research Ltd
Date: 09-07-2020
DOI: 10.12688/F1000RESEARCH.25234.1
Abstract: Tissue-resident immune cells stably localize in tissues largely independent of the circulatory system. While initial studies have focused on the recognition of CD8 + tissue-resident memory T (CD8 T RM ) cells, it is now clear that numerous cell types such as CD4 + T cells, gd T cells, innate lymphoid cells and mucosal-associated invariant T (MAIT) cells form stable populations in tissues. They are enriched at the barrier surfaces and within non-lymphoid compartments. They provide an extensive immune network capable of sensing local perturbations of the body’s homeostasis. This positioning enables immune cells to positively influence immune protection against infection and cancer but paradoxically also augment autoimmunity, allergy and chronic inflammatory diseases. Here, we highlight the recent studies across multiple lymphoid immune cell types that have emerged on this research topic and extend our understanding of this important cellular network. In addition, we highlight the areas that remain gaps in our knowledge of the regulation of these cells and how a deeper understanding may result in new ways to ‘target’ these cells to influence disease outcome and treatments.
Id2-mediated inhibition of E2A represses memory CD8+ T cell differentiation
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.
Immunology & Cell Biology Publication of the Year Awards 2014
Publisher: Wiley
Date: 11-2015
DOI: 10.1038/ICB.2015.86
Unusual suspects: dancing with stromal cells
Publisher: Springer Science and Business Media LLC
Date: 06-2017
DOI: 10.1038/NI.3741
Author Correction: The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity
Publisher: Springer Science and Business Media LLC
Date: 30-01-2020
DOI: 10.1038/S41590-020-0606-8
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells
Publisher: Springer Science and Business Media LLC
Date: 02-09-2007
DOI: 10.1038/NI1505
Abstract: Of the many dendritic cell (DC) subsets, DCs expressing the monomorphic coreceptor CD8 alpha-chain (CD8alpha) are localized permanently in lymphoid organs, whereas 'tissue-derived DCs' remain in nonlymphoid tissues until they 'capture' antigen and then move to local lymph nodes. Here we show that after lung infection, both naive and memory CD8+ 'killer' T cells responded to influenza virus antigens presented by lymph node-resident CD8alpha+ DCs, but only naive cells responded to antigens presented by lung-derived DCs. This difference provides a mechanism for priming naive T cell responses in conditions in which robust memory predominates. Our findings have implications for immunity to pathogens that can mutate their T cell epitopes, such as influenza virus and human immunodeficiency virus, and challenge the long-held view that memory T cells have less-stringent requirements for activation than naive T cells have.
Compromised influenza virus-specific CD8+-T-cell memory in CD4+-T-cell-deficient mice
Publisher: American Society for Microbiology
Date: 12-2002
DOI: 10.1128/JVI.76.23.12388-12393.2002
Abstract: The primary influenza A virus-specific CD8 + -T-cell responses measured by tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL) lymphocyte populations were similar in magnitude for conventional I-A b +/+ and CD4 + -T-cell-deficient I-A b −/− mice. Comparable levels of virus-specific cytotoxic-T-lymphocyte activity were detected in the inflammatory exudate recovered by BAL following challenge. However, both the size of the memory T-cell pool and the magnitude of the recall response in the lymphoid tissues (but not the BAL specimens) were significantly diminished in mice lacking the CD4 + subset. Also, the rate of virus elimination from the infected respiratory tract slowed at low virus loads following challenge of naïve and previously immunized I-A b −/− mice. Thus, though the capacity to mediate the CD8 + -T-cell effector function is broadly preserved in the absence of concurrent CD4 + -T-cell help, both the maintenance and recall of memory are compromised and the clearance of residual virus is delayed. These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection.
Development, homeostasis, and heterogeneity of NK cells and ILC1
Publisher: Springer International Publishing
Date: 2016
DOI: 10.1007/82_2015_474
Abstract: Natural killer (NK) cells are a population of cytotoxic innate lymphocytes that evolved prior to their adaptive counterparts and constitute one of the first lines of defense against infected or mutated cells. NK cells are rapidly activated, expressing an array of germ-line encoded receptors that allow them to scan for protein irregularities on cells and kill those deemed "altered-self." NK cells rapidly produce a broad range of cytokines and chemokines following activation by virus, bacterial, or parasitic infection and are thus key in orchestrating inflammation. NK cells have previously been viewed to represent a relatively homogeneous group of IFN-γ-producing cells that express the surface markers NK1.1 and natural killer cell p46-related protein (NKp46 or NCR1 encoded by Ncr1) and depend on the transcription factor T-bet for their development. Recently, a second subset of T-bet-dependent innate cells, the group 1 innate lymphoid cells (ILC1), has been discovered which share many attributes of conventional NK (cNK) cells. Despite the similarities between ILC1 and cNK cells , they differ in several important aspects including their localization, transcriptional regulation, and phenotype suggesting each subset has distinct origins and functions in immune responses. Previously, the ability to detect and spontaneously kill cells that exhibit "altered-self" which is central to tumor and viral immunity has been thought to be an attribute restricted solely to cNK cells. The identification of ILC1 challenges this notion and suggests that key contributions from ILC1 may have gone unrecognized. Thus, understanding the different rules that govern the behavior of ILC1 and cNK cells in immune responses may potentially open unexpected doorways to uncover novel strategies to manipulate these cells in treating disease. Here, we review recent advances in our understanding of peripheral cNK cell and ILC1 heterogeneity in terms of their development, phenotype, homeostasis, and effector functions.
Acetylation of the Cd8 Locus by KAT6A Determines Memory T Cell Diversity
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.
Lethal giant larvae‐1 deficiency enhances the CD8+ effector T‐cell response to antigen challenge in vivo
Publisher: Wiley
Date: 22-09-2015
DOI: 10.1038/ICB.2015.82
Abstract: Lethal giant larvae-1 (Lgl-1) is an evolutionary conserved protein that regulates cell polarity in erse lineages however, the role of Lgl-1 in the polarity and function of immune cells remains to be elucidated. To assess the role of Lgl-1 in T cells, we generated chimeric mice with a hematopoietic system deficient for Lgl-1. Lgl-1 deficiency did not impair the activation or function of peripheral CD8(+) T cells in response to antigen presentation in vitro, but did skew effector and memory T-cell differentiation. When challenged with antigen-expressing virus or tumor, Lgl-1-deficient mice displayed altered T-cell responses. This manifested in a stronger antiviral and antitumor effector CD8(+) T-cell response, the latter resulting in enhanced control of MC38-OVA tumors. These results reveal a novel role for Lgl-1 in the regulation of virus-specific T-cell responses and antitumor immunity.
Bach2: An Instrument of Heterogeneity for Long-Term Protection.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.IMMUNI.2018.03.033
Abstract: Generation of functionally erse effector and memory killer T cells is essential for immediate and long-term protective immunity. Herndler-Brandstetter et al. (2018) report that Bach2 promotes functional plasticity of effector T cells and the transition into the long-term memory compartment by regulating the expression of the inhibitory receptor KLRG1.
Identification of the earliest NK-cell precursor in the mouse BM
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.
Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-11-2014
Abstract: T cell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how T cells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that T cell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, ision fate, whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear ision calculus, allowing the strength of a T cell response to be predicted from the sum of the underlying signal components. These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.
Differential requirement for Nfil3 during NK cell development
Publisher: The American Association of Immunologists
Date: 15-03-2014
Abstract: NK cells can be grouped into distinct subsets that are localized to different organs and exhibit a different capacity to secrete cytokines and mediate cytotoxicity. Despite these hallmarks that reflect tissue-specific specialization in NK cells, little is known about the factors that control the development of these distinct subsets. The basic leucine zipper transcription factor Nfil3 (E4bp4) is essential for bone marrow–derived NK cell development, but it is not clear whether Nfil3 is equally important for all NK cell subsets or how it induces NK lineage commitment. In this article, we show that Nfil3 is required for the formation of Eomes-expressing NK cells, including conventional medullary and thymic NK cells, whereas TRAIL+ Eomes− NK cells develop independently of Nfil3. Loss of Nfil3 during the development of bone marrow–derived NK cells resulted in reduced expression of Eomes and, conversely, restoration of Eomes expression in Nfil3−/− progenitors rescued NK cell development and maturation. Collectively, these findings demonstrate that Nfil3 drives the formation of mature NK cells by inducing Eomes expression and reveal the differential requirements of NK cell subsets for Nfil3.
Confocal laser endomicroscopy to monitor the colonic mucosa of mice.
Publisher: Elsevier BV
Date: 06-2015
CD4+ T cells specific for a model latency-associated antigen fail to control a gammaherpesvirusin vivo
Publisher: Wiley
Date: 12-2006
Abstract: CD4(+) T cells play a major role in containing herpesvirus infections. However, their cellular targets remain poorly defined. In vitro CD4(+) T cells have been reported to kill B cells that harbor a latent gammaherpesvirus. We used the B cell-tropic murine gammaherpesvirus-68 (MHV-68) to test whether this also occurred in vivo. MHV-68 that expressed cytoplasmic ovalbumin (OVA) in tandem with its episome maintenance protein, ORF73, stimulated CD8(+) T cells specific for the H2-K(b)-restricted OVA epitope SIINFEKL and was rapidly eliminated from C57BL/6 (H2(b)) mice. However, the same virus failed to stimulate CD4(+) T cells specific for the I-A(d)/I-A(b)-restricted OVA(323-339) epitope. We overcame any barrier to the MHC class II-restricted presentation of an endogenous epitope by substituting OVA(323-339) for the CLIP peptide of the invariant chain (ORF73-IRES-Ii-OVA), again expressed in tandem with ORF73. This virus presented OVA(323-339) but showed little or no latency deficit in either BALB/c (H2(d)) or C57BL/6 mice. Latent antigen-specific CD4(+) T cells therefore either failed to recognize key virus-infected cell populations in vivo or lacked the effector functions required to control them.
The transcription factor T-bet is essential for the development of NKp46 + innate lymphocytes via the Notch pathway
Publisher: Springer Science and Business Media LLC
Date: 03-03-2013
DOI: 10.1038/NI.2545
Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway
Publisher: Springer Science and Business Media LLC
Date: 29-09-2016
DOI: 10.1038/NATURE20105
Abstract: Innate lymphoid cells (ILCs) functionally resemble T lymphocytes in cytotoxicity and cytokine production but lack antigen-specific receptors, and they are important regulators of immune responses and tissue homeostasis. ILCs are generated from common lymphoid progenitors, which are subsequently committed to innate lymphoid lineages in the α-lymphoid progenitor, early innate lymphoid progenitor, common helper innate lymphoid progenitor and innate lymphoid cell progenitor compartments. ILCs consist of conventional natural killer cells and helper-like cells (ILC1, ILC2 and ILC3). Despite recent advances, the cellular heterogeneity, developmental trajectory and signalling dependence of ILC progenitors are not fully understood. Here, using single-cell RNA-sequencing (scRNA-seq) of mouse bone marrow progenitors, we reveal ILC precursor subsets, delineate distinct ILC development stages and pathways, and report that high expression of programmed death 1 (PD-1
Contribution of Thy1+ NK cells to protective IFN-γ production during Salmonella Typhimurium infections
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2013
Abstract: IFN-γ is critical for immunity against infections with intracellular pathogens, such as Salmonella enterica . However, which of the many cell types capable of producing IFN-γ controls Salmonella infections remains unclear. Using a mouse model of systemic Salmonella infection, we observed that only a lack of all lymphocytes or CD90 (Thy1) + cells, but not the absence of T cells, Retinoic acid-related orphan receptor (ROR)-γt–dependent lymphocytes, (NK)1.1 + cells, natural killer T (NKT), and/or B cells alone, replicated the highly susceptible phenotype of IFN-γ–deficient mice to Salmonella infection. A combination of antibody depletions and adoptive transfer experiments revealed that early protective IFN-γ was provided by Thy1-expressing natural killer (NK) cells and that these cells improved antibacterial immunity through the provision of IFN-γ. Further analysis of NK cells producing IFN-γ in response to Salmonella indicated that less mature NK cells were more efficient at mediating antibacterial effector function than terminally differentiated NK cells. Inspired by recent reports of Thy1 + NK cells contributing to immune memory, we analyzed their role in secondary protection against otherwise lethal WT Salmonella infections. Notably, we observed that a newly generated Salmonella vaccine strain not only conferred superior protection compared with conventional regimens but that this enhanced efficiency of recall immunity was afforded by incorporating CD4 − CD8 − Thy1 + cells into the secondary response. Taken together, these findings demonstrate that Thy1-expressing NK cells play an important role in antibacterial immunity.
Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection
Publisher: Wiley
Date: 07-10-2018
DOI: 10.1111/IMR.12709
The NF-[kappa]B1 transcription factor prevents the intrathymic development of CD8 T cells with memory properties
Publisher: Wiley
Date: 29-11-2012
Innate Lymphoid Cells in Colorectal Cancers: A Double-Edged Sword.
Publisher: Frontiers Media SA
Date: 15-01-2019
Supplementary Tables from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22430400.V1
Abstract: Supplementary tables
Terminal Differentiation of Dendritic Cells
Publisher: Elsevier
Date: 2013
Parallel worlds of the adaptive and innate immune cell networks.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.COI.2019.04.008
Abstract: Adaptive and innate immune cells have typically been functionally and temporally segregated even though they share a number of salient features. Over the past decade, significant advances have been made in understanding the composition and ersity of both innate and adaptive cell populations. This has shed light on how cells from two distinct pathways are so highly complementary. Innate lymphoid cells (ILCs) are pivotally positioned in tissues to form a stable population akin to tissue-resident T cells that protects the body. Nevertheless, the pathway by which different lymphocytes enter tissues, terminally differentiate and are replenished to maintain populations remains incompletely understood. Recent evidence challenges our assumptions about the sedentary lifestyles of so called 'tissue-resident cells' and pushes us to consider their roles in orchestrating protection of the immune system beyond the classical models.
Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells
Publisher: Springer Science and Business Media LLC
Date: 12-10-2008
DOI: 10.1038/NI.1665
Abstract: The importance of conventional dendritic cells (cDCs) in the processing and presentation of antigen is well established, but the contribution of plasmacytoid dendritic cells (pDCs) to these processes, and hence to T cell immunity, remains unclear. Here we showed that unlike cDCs, pDCs continued to synthesize major histocompatibility complex (MHC) class II molecules and the MHC class II ubiquitin ligase MARCH1 long after activation. Sustained MHC class II-peptide complex formation, ubiquitination and turnover rendered pDCs inefficient in the presentation of exogenous antigens but enabled pDCs to continuously present endogenous viral antigens in their activated state. As the antigen-presenting abilities of cDCs and pDCs are fundamentally distinct, these two cell types may activate largely nonoverlapping repertoires of CD4(+) T cells.
Transcriptomic profiling of cardiac tissues from SARS‐CoV‐2 patients identifies DNA damage
Publisher: Wiley
Date: 27-09-2023
DOI: 10.1111/IMM.13577
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is known to present with pulmonary and extra‐pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS‐CoV‐2 infection is likely to lead to more severe disease, with multi‐organ effects, including cardiovascular disease. SARS‐CoV‐2 has been associated with acute and long‐term cardiovascular disease, but the molecular changes that govern this remain unknown. In this study, we investigated the host transcriptome landscape of cardiac tissues collected at rapid autopsy from seven SARS‐CoV‐2, two pH1N1, and six control patients using targeted spatial transcriptomics approaches. Although SARS‐CoV‐2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1‐like macrophage infiltration in the cardiac tissues of COVID‐19 patients. The DNA damage present in the SARS‐CoV‐2 patient s les, were further confirmed by γ‐H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of interferon‐stimulated genes, in particular interferon and complement pathways, when compared with COVID‐19 patients. These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS‐CoV‐2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra‐pulmonary organs, including the cardiovascular system of COVID‐19 patients, to delineate the immunopathobiology of SARS‐CoV‐2 infection, and long term impact on health.
Innate lymphoid cells: potential targets for cancer therapeutics
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.TRECAN.2022.10.007
Abstract: Innate lymphoid cells (ILCs) comprise a number of different subsets, including natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells that express receptors and signaling pathways that are highly responsive to continuously changing microenvironmental cues. In this Review, we highlight the key features of innate cells that define their capacity to respond rapidly to different environments, how this ability can drive both tumor protection (limiting tumor development) or, alternatively, tumor progression, promoting tumor dissemination and resistance to immunotherapy. We discuss how understanding the regulation of ILCs that can detect tumor cells early in a response opens the possibility of exploiting this functional plasticity to develop rational therapeutic strategies to bolster adaptive immune responses and improve patient outcomes.
An epigenetic silencing pathway controlling T helper 2 cell lineage commitment
Publisher: Springer Science and Business Media LLC
Date: 07-2012
DOI: 10.1038/NATURE11173
Abstract: During immune responses, naive CD4+ T cells differentiate into several T helper (TH) cell subsets under the control of lineage-specifying genes. These subsets (TH1, TH2 and TH17 cells and regulatory T cells) secrete distinct cytokines and are involved in protection against different types of infection. Epigenetic mechanisms are involved in the regulation of these developmental programs, and correlations have been drawn between the levels of particular epigenetic marks and the activity or silencing of specifying genes during differentiation. Nevertheless, the functional relevance of the epigenetic pathways involved in TH cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1–H3K9me3–HP1α silencing pathway in the control of TH2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethylation of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1α (HP1α) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. We now propose that the SUV39H1–H3K9me3–HP1α pathway participates in maintaining the silencing of TH1 loci, ensuring TH2 lineage stability. In TH2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1α at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1α-deficient TH2 cells, in contrast to wild-type cells, expressed TH1 genes when recultured under conditions that drive differentiation into TH1 cells. In a mouse model of TH2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards TH1 responses and decreased the lung pathology. These results establish a link between the SUV39H1–H3K9me3–HP1α pathway and the stability of TH2 cells, and they identify potential targets for therapeutic intervention in TH2-cell-mediated inflammatory diseases.
Systemic administration of IL‐33 induces a population of circulating KLRG1hi type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma
Publisher: Wiley
Date: 18-09-2020
DOI: 10.1111/IMCB.12390
TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis
Publisher: Rockefeller University Press
Date: 29-05-2015
DOI: 10.1084/JEM.20181778
Abstract: Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.
Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-04-2016
Abstract: The immune system fights microbial invaders by maintaining multiple lines of defense. For instance, specialized memory T cells [resident memory T cells (T rms )] colonize portals of pathogen entry, such as the skin, lung, and gut, to quickly halt reinfections. Mackay et al. now report that in mice, T rms as well as other tissue-dwelling lymphocyte populations such as natural killer cells share a common transcriptional program driven by the related transcription factors Hobit and Blimp1. Tissue residency and retention of lymphocytes require expression of Hobit and Blimp1, which, among other functions, suppress genes that promote tissue exit. Science , this issue p. 459
CARD11 is dispensable for homeostatic responses and suppressive activity of peripherally-induced FOXP3+ regulatory T cells.
Publisher: Wiley
Date: 26-06-2019
DOI: 10.1111/IMCB.12268
Abstract: FOXP3
Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells
Publisher: Public Library of Science (PLoS)
Date: 10-11-2011
DC Migration: Hard-Wired for T Cell Activation
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.IMMUNI.2008.08.003
Abstract: Dendritic cells (DCs) play a central role in responding to pathogens. In this issue of Immunity, Aoshi et al. (2008) highlight the fact that the migratory route DCs take to drive T cell activation is independent of the architecture of lymphoid tissues.
The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15
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.
Virus-specific and bystander CD8+ T-cell proliferation in the acute and persistent phases of a gammaherpesvirus infection
Publisher: American Society for Microbiology
Date: 05-2001
DOI: 10.1128/JVI.75.9.4435-4438.2001
Abstract: The cycling characteristics of CD8 + T cells specific for two lytic-phase epitopes of murine gammaherpesvirus 68 (γHV68) have been analyzed for mice with high or low levels of virus persistence. The extent of cell ision is generally reflective of the antigen load and suggests that γHV68 may be regularly reactivating from latency for some months after the resolution of the acute phase of the infectious process. Although γHV68 infection is also associated with massive proliferation of lymphocytes that are not obviously specific for the virus, the level of “bystander-induced” cycling in a population of influenza virus-specific CD8 + T cells was generally fourfold lower than the extent of cell ision seen for the antigen-driven, γHV68-specific response. The overall conclusion is that turnover rates substantially in excess of 5 to 10% over 6 days for CD8 + “memory” T-cell populations are likely to be reflective of continued antigenic exposure.
Blimp1: Driving terminal differentiation to a T
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.
Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2022
DOI: 10.1101/2022.03.24.22272732
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes govern this remain unknown. In this study, we investigated the landscape of cardiac tissues collected at rapid autopsy from SARS-CoV-2, pH1N1, and control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients. The DNA damage present in the SARS-CoV-2 patient s les, were further confirmed by γ−H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of Interferon-stimulated genes (ISGs), in particular interferon and complement pathways, when compared with COVID-19 patients. These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra-pulmonary organs, including the cardiovascular system of COVID-19 patients, to delineate the immunopathobiology of SARS-CoV-2 infection, and long term impact on health.
Granzyme M has a critical role in providing innate immune protection in ulcerative colitis
Publisher: Springer Science and Business Media LLC
Date: 21-07-2016
Abstract: Inflammatory bowel disease (IBD) is an immunoregulatory disorder, associated with a chronic and inappropriate mucosal immune response to commensal bacteria, underlying disease states such as ulcerative colitis (UC) and Crohn’s disease (CD) in humans. Granzyme M (GrzM) is a serine protease expressed by cytotoxic lymphocytes, in particular natural killer (NK) cells. Granzymes are thought to be involved in triggering cell death in eukaryotic target cells however, some evidence supports their role in inflammation. The role of GrzM in the innate immune response to mucosal inflammation has never been examined. Here, we discover that patients with UC, unlike patients with CD, display high levels of GrzM mRNA expression in the inflamed colon. By taking advantage of well-established models of experimental UC, we revealed that GrzM-deficient mice have greater levels of inflammatory indicators during dextran sulfate sodium (DSS)-induced IBD, including increased weight loss, greater colon length reduction and more severe intestinal histopathology. The absence of GrzM expression also had effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease. These findings demonstrate, for the first time, that GrzM has a critical role during early stages of inflammation in UC, and that in its absence colonic inflammation is enhanced.
Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development
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.
Profiling of lung SARS-CoV-2 and influenza virus infection dissects virus-specific host responses and gene signatures
Publisher: European Respiratory Society (ERS)
Date: 21-10-2022
DOI: 10.1183/13993003.01881-2021
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies. Here, we use targeted transcriptomics of formalin-fixed paraffin-embedded tissue using the NanoString GeoMX platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients. Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the s le, within patient correlations and patient–patient variation, had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27 , previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.
Supplementary Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22430403
Abstract: Supplementary Methods and Data- Changes are unmarked
Fas ligand–mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas
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.
A role for the mitochondrial protein Mrpl44 in maintaining OXPHOS capacity
Publisher: Public Library of Science (PLoS)
Date: 29-07-2015
Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity.
Publisher: Elsevier BV
Date: 02-2008
Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-11-2003
Abstract: We used mutant Fas-deficient ( lpr ) or Bim-deficient mice to investigate the role of the death receptor and Bcl-2-regulated apoptotic pathways in terminating a physiological T cell response to herpes simplex virus infection. In WT and lpr mice CD8 + antigen-specific T cells were deleted after viral clearance. In contrast, the immune response was not terminated in Bim-deficient mice despite viral clearance, and CD8 + antigen-specific T cells accumulated in the spleen. Thus, Bim is dispensable for viral clearance but is necessary for the death of activated T cells when immune responses are terminated. These findings have implications for the therapeutic manipulation of immune responses to infections and immunization.
Membrane association of a model CD4+ T-cell vaccine antigen confers enhanced yet incomplete protection against murid herpesvirus-4 infection
Publisher: Wiley
Date: 29-02-2020
DOI: 10.1111/IMCB.12319
Abstract: Vaccination against γ-herpesviruses has proved difficult. CD4
Supplementary Tables from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22430400
Abstract: Supplementary tables
Monocyte-Derived Dendritic Cells: A Transendothelial Trip Launches the Quest To Understand Heterogeneity in the APC Family
Publisher: The American Association of Immunologists
Date: 06-2017
miR-142 keeps CD4+ DCs in balance
Publisher: American Society of Hematology
Date: 07-02-2013
4th Australasian Vaccines and Immunotherapeutic Development Meeting
Publisher: Wiley
Date: 11-2012
DOI: 10.1038/ICB.2012.55
Abstract: This report describes advances in the understanding of how we might intervene in destructive processes, such as autoimmunity, infectious disease and cancer, through the development of innovative vaccines and immunotherapeutics.
c-Myb is required for plasma cell migration to bone marrow after immunization or infection.
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.
Erratum: The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells (Nature Immunology (2013) 14 (1155-1165 ))
Publisher: Springer Science and Business Media LLC
Date: 19-08-2014
DOI: 10.1038/NI0914-894B
DCs as targets for vaccine design
Publisher: Elsevier BV
Date: 04-2004
Interference with dendritic cell populations limits early antigen presentation in chronic γ-herpesvirus-68 infection
Publisher: The American Association of Immunologists
Date: 15-09-2010
Abstract: A critical factor influencing the ability of the host to mount a robust immune response against a virus depends on the rapid recruitment of dendritic cells (DCs) presenting Ags. From the outset, this step sets the tempo for subsequent activation of virus-specific T cells. Despite this, how induction of the immune response might be modified by pathogens with the capacity to establish persistence is unclear. In this study, we have characterized the in vivo influence of murine γ-herpesvirus K3-mediated interference with MHC class I in DCs that drive the initial adaptive immune response. We observed that γ-herpesvirus could interfere with the very earliest phase of Ag presentation through K3 by directly targeting migratory and lymph node-resident DCs. These results show that a pathogen with the capacity to interfere with early Ag presentation can establish suboptimal conditions for rapid induction of the adaptive immune response and thus favor establishment of viral persistence.
Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8α+ dendritic cells
Publisher: Proceedings of the National Academy of Sciences
Date: 23-09-2008
Abstract: Although CD8 + T cells do not contribute to protection against the blood stage of Plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ECM). At present, there is no direct evidence that the CD8 + T cells mediating ECM are parasite-specific or, for that matter, whether parasite-specific CD8 + T cells are generated in response to blood-stage infection. To resolve this and to define the cellular requirements for such priming, we generated transgenic P. berghei parasites expressing model T cell epitopes. This approach was necessary as MHC class I-restricted antigens to blood-stage infection have not been defined. Here, we show that blood-stage infection leads to parasite-specific CD8 + and CD4 + T cell responses. Furthermore, we show that P. berghei -expressed antigens are cross-presented by the CD8α + subset of dendritic cells (DC), and that this induces pathogen-specific cytotoxic T lymphocytes (CTL) capable of lysing cells presenting antigens expressed by blood-stage parasites. Finally, using three different experimental approaches, we provide evidence that CTL specific for parasite-expressed antigens contribute to ECM.
Supplementary Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22430403.V1
Abstract: Supplementary Methods and Data- Changes are unmarked
Inert 50-nm polystyrene nanoparticles that modify pulmonary dendritic cell function and inhibit allergic airway inflammation
Publisher: The American Association of Immunologists
Date: 02-2012
Abstract: Nanoparticles are being developed for erse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c+MHCIIhi DCs in the lung and draining LN and allergen-laden CD11bhiMHCIIhi DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11bhi DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4+ T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.
IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study
Publisher: Cold Spring Harbor Laboratory
Date: 11-2021
DOI: 10.1101/2021.10.29.21265555
Abstract: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 ( IFI27 ) in COVID-19 patients. We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For ex le, in the pandemic H1N1/09 swine influenza virus infection, IFI27- like genes were highly upregulated in the blood s les of severely infected patients. These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus. We searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms “ IFI27 ”, “COVID-19, “gene expression” and “outcome prediction”. We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of “gene expression” and “COVID-19”, IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19 none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic. Here, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27 , could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic. This is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.
Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Publisher: American Association for Cancer Research (AACR)
Date: 24-08-2021
DOI: 10.1158/0008-5472.CAN-21-0839
Abstract: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.
Shaping Innate Lymphoid Cell Diversity.
Publisher: Frontiers Media SA
Date: 16-11-2017
A role for plasmacytoid dendritic cells in the rapid IL-18-dependent activation of NK cells following HSV-1 infection
Publisher: Wiley
Date: 19-04-2007
Complexity of cytokine network regulation of innate lymphoid cells in protective immunity.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.CYTO.2014.06.002
Abstract: The body's surface provides a critical barrier shielding us from various mechanical and pathogenic insults by virtue of the physical protection it provides and the presence of specialized populations of innate lymphoid cells (ILCs) that sense inflammatory signals induced by pathogens. This response plays a central role in the development and activation of early immune responses. While ILCs depend on common γ-chain cytokine signaling for their development, an essential component of the armory of these cells is their capacity to produce defensive cytokines when activated by viruses, microbes and other parasites. In this review, we describe the multiple intrinsic and extrinsic pathways that comprise the cytokine circuitry regulating the development and function of ILC necessary for protective immunity.
Peripheral natural killer cell maturation depends on the transcription factor Aiolos.
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.
T-helper 22 cells develop as a distinct lineage from Th17 cells during bacterial infection and phenotypic stability is regulated by T-bet
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1038/S41385-021-00414-6
Abstract: CD4
The epithelium of canine palatine tonsils
Publisher: Springer Science and Business Media LLC
Date: 08-1995
DOI: 10.1007/BF00186007
Immunology and Cell Biology Publication of the Year Awards 2010
Publisher: Wiley
Date: 10-2011
DOI: 10.1038/ICB.2011.77
Batf3 selectively determines acquisition of CD8 + dendritic cell phenotype and function
Publisher: Wiley
Date: 29-11-2017
DOI: 10.1038/ICB.2016.83
Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory
Publisher: Springer Science and Business Media LLC
Date: 12-10-2020
ISCOMATRIX vaccines mediate CD8+ T‐cell cross‐priming by a MyD88‐dependent signaling pathway
Publisher: Wiley
Date: 06-09-2011
DOI: 10.1038/ICB.2011.71
Immunology & Cell Biology Publication of the Year Awards 2015
Publisher: Wiley
Date: 11-2016
DOI: 10.1038/ICB.2016.86
Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
Membrane-bound Fas ligand only is essential for Fas-induced apoptosis
Publisher: Springer Science and Business Media LLC
Date: 10-2009
DOI: 10.1038/NATURE08402
Dendritic cells: Driving the differentiation programme of T cells in viral infections
Publisher: Wiley
Date: 18-03-2008
DOI: 10.1038/ICB.2008.15
Abstract: Protective immunity against viral pathogens depends on the generation and maintenance of a small population of memory CD8(+) T cells. Successful memory cell generation begins with early interactions between naïve T cell and dendritic cells (DCs) within the inflammatory milieu of the secondary lymphoid tissues. Recent insights into the role of different populations of DCs, and kinetics of antigen presentation, during viral infections have helped to understand how DCs can shape the immune response. Here, we review the recent progress that has been made towards defining how specific DC subsets drive effector CD8(+) T-cell expansion and differentiation into memory cells. Further, we endeavour to examine how the molecular signals imparted by DCs coordinate to generate protective CD8(+) T-cell immunity.
Interleukin-2 Tickles T Cell Memory
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.IMMUNI.2010.01.009
Abstract: The differentiation of peripheral T lymphocytes depends on interactions between intrinsic and extrinsic factors. In this issue of Immunity, Pipkin et al. (2010) and Kalia et al. (2010) link differential interleukin-2 signaling and inflammation with the transcriptional events leading to the development of effector and memory cells.
Getting together: Dendritic cells, T cells, collaboration and fates
Publisher: Wiley
Date: 06-2008
DOI: 10.1038/ICB.2008.18
Gutsy sensations modulate intestinal disease
Publisher: Elsevier BV
Date: 2023
Assessing the role of the T-box transcription factor Eomes in B cell differentiation during either Th1 or Th2 cell-biased responses.
Publisher: Public Library of Science (PLoS)
Date: 06-12-2018
Diversity of Epitope and Cytokine Profiles for Primary and Secondary Influenza A Virus-Specific CD8+ T Cell Responses
Publisher: The American Association of Immunologists
Date: 04-2001
DOI: 10.4049/JIMMUNOL.166.7.4627
Abstract: Screening with the flow cytometric IFN-γ assay has led to the identification of a new immunogenic peptide (SSYRRVPGI) from the influenza PB1 polymerase (PB1703–711) and a mimotope (ISPLMVAYM) from the PB2 polymerase (PB2198–206). CD8+ T cells specific for KbPB1703 make both IFN-γ and TNF-α following stimulation with both peptides. The CD8+ KbPB1703+ population kills PB2198-pulsed targets, but cell lines stimulated with PB2198 neither bind the KbPB1703 tetramer nor become CTL. This CD8+KbPB1703+ population is prominent in the primary response to an H3N2 virus, although it is much less obvious following secondary challenge of H1N1-primed mice. Even so, we can now account for & % of the CD8+ T cells in a primary influenza pneumonia and & % of those present after H3N2 → H1N1 challenge. Profiles of IFN-γ and TNF-α staining following in vitro stimulation have been traced for the four most prominent influenza peptides through primary and secondary responses into long-term memory. The DbNP366 epitope that is immunodominant after the H3N2 → H1N1 challenge shows the lowest frequencies of CD8+ IFN-γ+TNF-α+ cells for & wk, and the intensity of IFN-γ staining is also low for the first 3 wk. By 11 wk, however, the IFN-γ/TNF-α profiles look to be similar for all four epitopes. At least by the criterion of cytokine production, there is considerable epitope-related functional ersity in the influenza virus-specific CD8+ T cell response. The results for the KbPB1703 epitope and the PB2198 mimotope also provide a cautionary tale for those using the cytokine staining approach to identity antigenic peptides.
Viral Neuraminidase Treatment of Dendritic Cells Enhances Antigen-Specific CD8+ T Cell Proliferation, but Does Not Account for the CD4+ T Cell Independence of the CD8+ T Cell Response during Influenza
Publisher: Elsevier BV
Date: 08-2001
Keeping memories alive
Publisher: Frontiers Media SA
Date: 2013
Survival and division fate programs are preserved but retuned during the naïve to memory CD8+ T‐cell transition
Publisher: Wiley
Date: 15-10-2023
DOI: 10.1111/IMCB.12699
Diversity, function, and transcriptional regulation of gut innate lymphocytes
Publisher: Frontiers Media SA
Date: 2013
The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway
Publisher: Springer Science and Business Media LLC
Date: 19-07-2013
DOI: 10.1038/NI0813-877B
The race between infection and immunity: how do pathogens set the pace?
Publisher: Elsevier BV
Date: 02-2009
Abstract: Infection is often referred to as a race between pathogen and immune response. This metaphor suggests that slower growing pathogens should be more easily controlled. However, a growing body of evidence shows that many chronic infections are caused by failure to control slow growing pathogens. The slow growth of pathogens seems to directly affect the kinetics of the immune response. Compared with the response to fast growing pathogens, the T-cell response to slow pathogens is delayed in its initiation, lymphocyte expansion is slow and the response often fails to clear the pathogen, leading to chronic infection. Understanding the 'rules of the race' for slow growing pathogens has important implications for vaccine design and immune control of many chronic infections.
SIDT1 Localizes to Endolysosomes and Mediates Double-Stranded RNA Transport into the Cytoplasm
Publisher: The American Association of Immunologists
Date: 15-06-2019
Abstract: dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear. In this study, we show that Sidt1 expression is upregulated in response to dsRNA and type I IFN exposure and that SIDT1 interacts with SIDT2. Moreover, similar to SIDT2, SIDT1 localizes to the endolysosomal compartment, interacts with the long dsRNA analog poly(I:C), and, when overexpressed, enhances endosomal escape of poly(I:C) in vitro. To elucidate the role of SIDT1 in vivo, we generated SIDT1-deficient mice. Similar to Sidt2−/− mice, SIDT1-deficient mice produced significantly less type I IFN following infection with HSV type 1. In contrast to Sidt2−/− mice, however, SIDT1-deficient animals showed no impairment in survival postinfection with either HSV type 1 or encephalomyocarditis virus. Consistent with this, we observed that, unlike SIDT2, tissue expression of SIDT1 was relatively restricted, suggesting that, whereas SIDT1 can transport extracellular dsRNA into the cytoplasm following endocytosis in vitro, the transport activity of SIDT2 is likely to be functionally dominant in vivo.
Shaping Naive and Memory Cd8+ T Cell Responses in Pathogen Infections Through Antigen Presentation
Publisher: Springer US
Date: 2007
Arginine methylation catalyzed by PRMT1 is required for B cell activation and differentiation.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1038/S41467-017-01009-1
Abstract: Arginine methylation catalyzed by protein arginine methyltransferases (PRMT) is a common post-translational modification in mammalian cells, regulating many important functions including cell signalling, proliferation and differentiation. Here we show the role of PRMT1 in B-cell activation and differentiation. PRMT1 expression and activity in human and mouse peripheral B cells increases in response to in vitro or in vivo activation. Deletion of the Prmt1 gene in mature B cells establishes that although the frequency and phenotype of peripheral B cell subsets seem unaffected, immune responses to T-cell-dependent and -independent antigens are substantially reduced. In vitro activation of Prmt1 -deficient B cells with a variety of mitogens results in diminished proliferation, differentiation and survival, effects that are correlated with altered signal transduction from the B cell receptor. Thus PRMT1 activity in B cells is required for correct execution of multiple processes that in turn are necessary for humoral immunity.
T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.IMMUNI.2015.11.008
Abstract: Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8(+)CD103(+) Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8(+)CD103(+) Trm cell development and survival.
CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2015
DOI: 10.1038/NCOMMS9644
Abstract: IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6 − CCR2 + ) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo . Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.
SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition.
Publisher: Elsevier BV
Date: 09-2017
The immunological functions of the Appendix: An example of redundancy?
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.SMIM.2018.02.005
Abstract: Biological redundancy ensures robustness in living organisms at several levels, from genes to organs. In this review, we explore the concept of redundancy and robustness through an analysis of the caecal appendix, an organ that is often considered to be a redundant remnant of evolution. However, phylogenic data show that the Appendix was selected during evolution and is unlikely to disappear once it appeared. In humans, it is highly conserved and malformations are extremely rare, suggesting a role for that structure. The Appendix could perform a dual role. First, it is a concentrate of lymphoid tissue resembling Peyer's patches and is the primary site for immunoglobulin A production which is crucial to regulate the density and quality of the intestinal flora. Second, given its shape and position, the Appendix could be a unique niche for commensal bacteria in the body. It is extremely rich in biofilms that continuously shed bacteria into the intestinal lumen. The Appendix contains a microbiota as erse as that found in the colon and could replenish the large intestine with healthy flora after a diarrhea episode. In conditions of modern medicine hygiene, and people live healthy without their appendix. However, several reports suggest that the effects of appendectomy could be subtler and associated with the development of inflammatory conditions such as inflammatory bowel disease (IBD), heart disease but also in less expected disorders such as Parkinson's disease. Lack of an Appendix also predicts a worsen outcome for recurrent Clostridium difficile infection, which is the first nosocomial infection in hospitals. Here, we review the literature and in combination with our own data, we suggest that the Appendix might be redundant in its immunological function but unique as a reservoir of microbiota.
Starvation suppresses T cell appetite
Publisher: Springer Science and Business Media LLC
Date: 21-05-2018
Characterisation of innate lymphoid cell populations at different sites in mice with defective T cell immunity
Publisher: F1000 Research Ltd
Date: 14-03-2018
DOI: 10.12688/WELLCOMEOPENRES.13199.3
Abstract: Background : Innate lymphoid cells (ILCs) have now been identified within most tissues of the body and current evidence indicates that this family of cells play a fundamental role in maintaining tissue homeostasis. However, few studies have compared the ILC populations between several tissues. Methods : We sought to generate a comprehensive characterisation of the ILC populations in different tissues of C57BL/6 WT and genetically modified mice targeting costimulatory pathways, using transcription factor expression to define specific groups. Results : Consistent with studies in idually describing the ILC composition in different tissues, our analysis revealed different ILC groups dominate the ILC population in different tissues. Additionally, we observed a population of IL-7Rα + Id2 + cells lacking expression of lineage markers but also lacking expression of GATA-3, RORgt or T-bet. This population was most evident in ear skin where it outnumbered the defined ILC groups, however, further experiments demonstrated that detection of these cells was influenced by how the tissue was digested, raising concerns as to its real nature. Since both ILC2 and ILC3 express ICOS, we then investigated the requirement for ICOS:ICOSL interactions in the homeostasis of ILC populations at these sites. Surprisingly, no significant differences were detected in the number of ILC1, ILC2 or ILC3 between WT and ICOSL -/- mice in any tissue, indicating that this pathway is not required for ILC homeostasis at these sites. These data were compared with CD80 -/- CD86 -/- mice given evidence of CD28 expression by some ILC and ILC crosstalk with activated T cells. Notably, the absence of CD28 ligands resulted in a significant increase in ILC2 and ILC3 numbers in the intestine. Conclusions : Together, these data provide new insight into ILC composition in different tissues in both WT and genetically modified mice where key costimulatory pathways are genetically deleted, providing a useful resource for further research into ILC biology.
Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-09-2003
Abstract: The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α + dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.
Nfil3 is required for the development of all innate lymphoid cell subsets
Publisher: Rockefeller University Press
Date: 04-08-2014
DOI: 10.1084/JEM.20140145
Abstract: Innate lymphoid cell (ILC) populations protect against infection and are essential for lymphoid tissue formation and tissue remodeling after damage. Nfil3 is implicated in the function of adaptive immune lineages and NK cell development, but it is not yet known if Nfil3 regulates other innate lymphoid lineages. Here, we identify that Nfil3 is essential for the development of Peyer’s patches and ILC2 and ILC3 subsets. Loss of Nfil3 selectively reduced Peyer’s patch formation and was accompanied by impaired recruitment and distribution of lymphocytes within the patches. ILC subsets exhibited high Nfil3 expression and genetic deletion of Nfil3 severely compromised the development of all subsets. Subsequently, Nfil3−/− mice were highly susceptible to disease when challenged with inflammatory or infectious agents. Thus, we demonstrate that Nfil3 is a key regulator of the development of ILC subsets essential for immune protection in the lung and gut.
Type I Interferons Direct Gammaherpesvirus Host Colonization
Publisher: Public Library of Science (PLoS)
Date: 25-05-2016
Pulmonary group 2 innate lymphoid cells: surprises and challenges.
Publisher: Elsevier BV
Date: 03-2019
A molecular threshold for effector CD8+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet
Publisher: Springer Science and Business Media LLC
Date: 07-03-2016
DOI: 10.1038/NI.3410
Blimp-1 connects the intrinsic and extrinsic regulation of T cell homeostasis
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.
Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.COI.2010.03.008
Abstract: CD8(+) T cells play a key role in protecting the body against invading microorganisms. Their capacity to control infection relies on the development of peripheral effector and memory T cells. Much of our current knowledge has been gained by tracking alterations of the phenotype of CD8(+) T cells but the molecular understanding of the events that underpin the emergence of heterogeneous effector and memory CD8(+) T cells in response to infection has remained limited. This review focuses on the recent progress in our understanding of the molecular wiring of this differentiation process.
TCF-1 controls ILC2 and NKp46+ RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation
Publisher: The American Association of Immunologists
Date: 15-10-2013
Abstract: Innate lymphocyte populations play a central role in conferring protective immunity at the mucosal frontier. In this study, we demonstrate that T cell factor 1 (TCF-1 encoded by Tcf7), a transcription factor also important for NK and T cell differentiation, is expressed by multiple innate lymphoid cell (ILC) subsets, including GATA3+ nuocytes (ILC2) and NKp46+ ILCs (ILC3), which confer protection against lung and intestinal inflammation. TCF-1 was intrinsically required for the differentiation of both ILC2 and NKp46+ ILC3. Loss of TCF-1 expression impaired the capacity of these ILC subsets to produce IL-5, IL-13, and IL-22 and resulted in crippled responses to intestinal infection with Citrobacter rodentium. Furthermore, a reduction in T-bet expression required for Notch-2–dependent development of NKp46+ ILC3 showed a dose-dependent reduction in TCF-1 expression. Collectively, our findings demonstrate an essential requirement for TCF-1 in ILC2 differentiation and reveal a link among Tcf7, Notch, and Tbx21 in NKp46+ ILC3 development.
Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks
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.
Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.CCELL.2016.05.019
Abstract: E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8 ) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8 ) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.
The role of dendritic cell subsets in selection between tolerance and immunity
Publisher: Wiley
Date: 10-2002
DOI: 10.1046/J.1440-1711.2002.01116.X
Abstract: Dendritic cells (DC) are considered nature's adjuvants. They are potent stimulators of naive T cells and key inducers of primary immune responses. In recent times it has become clear that they can also play a central role in the development of T cell tolerance. Further complicating our understanding of DC function is the realization that DC can no longer be viewed as a homogeneous cell type. Rather, they exist as a complex mixture of strikingly different cell populations. The mechanisms that drive the conflicting immunological outcomes of tolerance and immunity have been the subject of intense scrutiny in recent years, most recently in terms of how the various DC subsets are involved in these events. Here we review recent experiments that provide insights into how DC subsets control the outcome of T cell activation and in so doing select between immunity and tolerance induction.
Selected Toll-like Receptor Ligands and Viruses Promote Helper-Independent Cytotoxic T Cell Priming by Upregulating CD40L on Dendritic Cells
Publisher: Elsevier BV
Date: 02-2009
Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment
Publisher: American Society of Hematology
Date: 24-12-2020
Abstract: Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.
Immunology and Cell Biology Publication of the Year Awards 2012
Publisher: Wiley
Date: 08-10-2013
DOI: 10.1038/ICB.2013.60
ILC2s masquerade as ILC1s to drive chronic disease
Publisher: Springer Science and Business Media LLC
Date: 19-05-2016
DOI: 10.1038/NI.3467
A Murid Gamma-Herpesviruses Exploits Normal Splenic Immune Communication Routes for Systemic Spread
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.CHOM.2014.03.010
Abstract: Gamma-herpesviruses (γHVs) are widespread oncogenic pathogens that chronically infect circulating lymphocytes. How they subvert the immune check-point function of the spleen to promote persistent infection is not clear. We show that Murid Herpesvirus-4 (MuHV-4) enters the spleen by infecting marginal zone (MZ) macrophages, which provided a conduit to MZ B cells. Relocation of MZ B cells to the white pulp allowed virus transfer to follicular dendritic cells. From here the virus reached germinal center B cells to establish persistent infection. Mice lacking MZ B cells, or treated with a sphingosine-1-phosphate receptor agonist to dislocate them, were protected against MuHV-4 colonization. MuHV-4 lacking ORF27, which encodes a glycoprotein necessary for efficient intercellular spread, could infect MZ macrophages but was impaired in long-term infection. Thus, MuHV-4, a γHV, exploits normal immune communication routes to spread by serial lymphoid/myeloid exchange.
Constitutive overexpression of TNF in BPSM1 mice causes iBALT and bone marrow nodular lymphocytic hyperplasia.
Publisher: Wiley
Date: 08-09-2018
DOI: 10.1111/IMCB.12197
Abstract: BPSM 1 (Bone phenotype spontaneous mutant 1) mice develop severe polyarthritis and heart valve disease as a result of a spontaneous mutation in the Tnf gene. In these mice, the insertion of a retrotransposon in the 3' untranslated region of Tnf causes a large increase in the expression of the cytokine. We have found that these mice also develop inducible bronchus‐associated lymphoid tissue ( iBALT ), as well as nodular lymphoid hyperplasia ( NLH ) in the bone marrow. Loss of TNFR 1 prevents the development of both types of follicles, but deficiency of TNFR 1 in the hematopoietic compartment only prevents the iBALT and not the NLH phenotype. We show that the development of arthritis and heart valve disease does not depend on the presence of the tertiary lymphoid tissues. Interestingly, while loss of IL ‐17 or IL ‐23 limits iBALT and NLH development to some extent, it has no effect on polyarthritis or heart valve disease in BPSM 1 mice.
Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus
Publisher: Proceedings of the National Academy of Sciences
Date: 26-05-2004
Abstract: During lung infection with virus, airway-derived dendritic cells (DC) have been thought to be the dominant cell type involved in acquisition, transport, and direct antigen presentation for cytotoxic T lymphocyte priming. Contrary to this view, we have found that both an airway-derived CD8α – CD11b – DC subset and distinct CD8α + lymph node resident DC can present class I-restricted antigens after lung infection with influenza virus or herpes simplex virus 1. Presentation by a nonairway-derived DC population argues that cytotoxic T lymphocyte priming may involve interplay between different DC subsets, not all of which originate within the site of infection.
Self-reactive and polyreactive B cells are generated and selected in the germinal center during γ-herpesvirus infection
Publisher: Oxford University Press (OUP)
Date: 27-08-2019
Abstract: Immune responses against certain viruses are accompanied by auto-antibody production although the origin of these infection-associated auto-antibodies is unclear. Here, we report that murine γ-herpesvirus 68 (MHV68)-induced auto-antibodies are derived from polyreactive B cells in the germinal center (GC) through the activity of short-lived plasmablasts. The analysis of recombinant antibodies from MHV68-infected mice revealed that about 40% of IgG+ GC B cells were self-reactive, with about half of them being polyreactive. On the other hand, virion-reactive clones accounted for only a minor proportion of IgG+ GC B cells, half of which also reacted with self-antigens. The self-reactivity of most polyreactive clones was dependent on somatic hypermutation (SHM), but this was dispensable for the reactivity of virus mono-specific clones. Furthermore, both virus-mono-specific and polyreactive clones were selected to differentiate to B220lo CD138+ plasma cells (PCs). However, the representation of GC-derived polyreactive clones was reduced and that of virus-mono-specific clones was markedly increased in terminally differentiated PCs as compared to transient plasmablasts. Collectively, our findings demonstrate that, during acute MHV68 infection, self-reactive B cells are generated through SHM and selected for further differentiation to short-lived plasmablasts but not terminally differentiated PCs.
Elucidating Specificity Opens a Window to the Complexity of Both the Innate and Adaptive Immune Systems
Publisher: Mary Ann Liebert Inc
Date: 04-2020
Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity
Publisher: Springer Science and Business Media LLC
Date: 10-10-2004
DOI: 10.1038/NI1129
Abstract: Several studies have indicated that CD8(+) T cells require CD4(+) T cell help for memory formation. Evidence suggests that such help can be antigen independent, challenging whether the 'licensing' of dendritic cells (DCs) by CD4(+) T cells is ever required for cytotoxic T lymphocyte (CTL) responses. We show here that help is essential for the generation of CTL immunity to herpes simplex virus 1 and that CD4(+) T cells mediate help in a cognate, antigen-specific way. We provide direct in vivo evidence for DC licensing by helper T cells and show that licensing is rapid and essential for the formation of effector and memory CTLs. In situations in which DCs are poorly licensed by pathogen-derived signals, our findings suggest that CTL immunity may be heavily dependent on cognate DC licensing.
Erratum: Transcriptional programming of the dendritic cell network (Nature Reviews Immunology (2012) 12 (101-113))
Publisher: Springer Science and Business Media LLC
Date: 25-01-2013
DOI: 10.1038/NRI3385
Modeling of Influenza-Specific CD8+ T Cells during the Primary Response Indicates that the Spleen Is a Major Source of Effectors
Publisher: The American Association of Immunologists
Date: 11-2011
Abstract: The biological parameters that determine the distribution of virus-specific CD8+ T cells during influenza infection are not all directly measurable by experimental techniques but can be inferred through mathematical modeling. Mechanistic and semimechanistic ordinary differential equations were developed to describe the expansion, trafficking, and disappearance of activated virus-specific CD8+ T cells in lymph nodes, spleens, and lungs of mice during primary influenza A infection. An intensive s ling of virus-specific CD8+ T cells from these three compartments was used to inform the models. Rigorous statistical fitting of the models to the experimental data allowed estimation of important biological parameters. Although the draining lymph node is the first tissue in which Ag-specific CD8+ T cells are detected, it was found that the spleen contributes the greatest number of effector CD8+ T cells to the lung, with rates of expansion and migration that exceeded those of the draining lymph node. In addition, models that were based on the number and kinetics of professional APCs fit the data better than those based on viral load, suggesting that the immune response is limited by Ag presentation rather than the amount of virus. Modeling also suggests that loss of effector T cells from the lung is significant and time dependent, increasing toward the end of the acute response. Together, these efforts provide a better understanding of the primary CD8+ T cell response to influenza infection, changing the view that the spleen plays a minor role in the primary immune response.
The dominant role of CD8+dendritic cells in cross-presentation is not dictated by antigen capture
Publisher: Proceedings of the National Academy of Sciences
Date: 11-07-2006
Abstract: Mouse spleens contain three populations of conventional (CD11c high ) dendritic cells (DCs) that play distinct functions. The CD8 + DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8 + DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8 + DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8 + and CD8 − DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8 + DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8 + DC but largely absent from CD8 − DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.
Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.IMMUNI.2017.06.021
Abstract: Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-β. Paralyzed DCs secreted TGF-β and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen-presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis- and trauma-induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention.
Transcriptional programming of the dendritic cell network
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.
B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1.
Publisher: Rockefeller University Press
Date: 08-10-2012
DOI: 10.1084/JEM.20111504
Abstract: A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4+ T cells into T follicular helper cells (TFH cells) during an immune response. TFH cells collaborate with B cells in the formation of germinal centers (GCs) during T cell–dependent antibody responses, in part through secretion of critical cytokines such as IL-21. In this study, we demonstrate that loss of either IL-6 or IL-21 has marginal effects on the generation of TFH cells and on the formation of GCs during the response to acute viral infection. However, mice lacking both IL-6 and IL-21 were unable to generate a robust TFH cell–dependent immune response. We found that IL-6 production in follicular B cells in the draining lymph node was an important early event during the antiviral response and that B cell–derived IL-6 was necessary and sufficient to induce IL-21 from CD4+ T cells in vitro and to support TFH cell development in vivo. Finally, the transcriptional activator Oct2 and its cofactor OBF-1 were identified as regulators of Il6 expression in B cells.
Id2 expression delineates differential checkpoints in the genetic program of CD8 alpha(+) and CD103(+) dendritic cell lineages
Publisher: Wiley
Date: 17-05-2011
Helper T cells, dendritic cells and CTL Immunity
Publisher: Wiley
Date: 02-2004
DOI: 10.1111/J.1440-1711.2004.01211.X
Abstract: In this review, we examine the emerging view that all CTL responses depend on CD4 T-cell help for the generation of efficient memory. We further review the evidence that CD4 and CD8 T cells must recognize antigen on the same dendritic cell, and examine why this corecognition is required. Earlier studies have suggested that CD4 T cells must activate the dendritic cell via CD40 to license it for the capacity to prime CTL immunity. More recently, however, CD40 signalling of the CTL has been reported. Here, we argue that the main reason for corecognition of antigen on the dendritic cell may be related to the time taken to activate and release CD4 and CD8 T cells from their priming dendritic cell. CD4 T cells may only be capable of activating one dendritic cell during the period that CD8 T cells are primed. In this case, corecognition of this same dendritic cell would be essential.
Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll‐like receptor signaling
Publisher: Wiley
Date: 20-11-2007
Abstract: Dendritic cells (DCs) play major roles in immunosurveillance. In peripheral tissues, 'immature' DCs are dedicated to capturing antigens. Detection of pathogens through Toll-like receptors (TLRs) triggers DC migration to the lymph nodes (LNs), where they acquire a 'mature' phenotype specialized at presenting antigens. However, DCs migrate from tissues and mature even in the absence of overt infections. This has been attributed to detection of commensal flora in the skin, the gut or other peripheral tissues in the steady state. To test this assumption, we have analyzed the DCs contained in the lymphoid organs of germ-free mice and of mice lacking the TLR adapter molecules, MyD88 and TRIF. We show that the proportion and expression of maturation markers in DC immigrants in the LNs of these mice are similar to those in normal mice. These results suggest that DC migration from tissues, followed by their phenotypic maturation, is regulated in the steady state by an inherent program of DC differentiation or by the release of low levels of inflammatory signals from normal tissues.
Tertiary lymphoid structures and B lymphocytes in cancer prognosis and response to immunotherapies
Publisher: Informa UK Limited
Date: 2021
RUNX2 Mediates Plasmacytoid Dendritic Cell Egress from the Bone Marrow and Controls Viral Immunity
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.
Bcl11b is essential for group 2 innate lymphoid cell development
Publisher: Rockefeller University Press
Date: 11-05-2015
DOI: 10.1084/JEM.20142224
Abstract: Group 2 innate lymphoid cells (ILC2s) are often found associated with mucosal surfaces where they contribute to protective immunity, inappropriate allergic responses, and tissue repair. Although we know they develop from a common lymphoid progenitor in the bone marrow (BM), the specific lineage path and transcriptional regulators that are involved are only starting to emerge. After ILC2 gene expression analysis we investigated the role of Bcl11b, a factor previously linked to T cell commitment, in ILC2 development. Using combined Bcl11b-tom and Id2-gfp reporter mice, we show that Bcl11b is expressed in ILC2 precursors in the BM and maintained in mature ILC2s. In vivo deletion of Bcl11b, by conditional tamoxifen-induced depletion or by Bcl11b−/− fetal liver chimera reconstitution, demonstrates that ILC2s are wholly dependent on Bcl11b for their development. Notably, in the absence of Bcl11b there is a concomitant expansion of the RORγt+ ILC3 population, suggesting that Bcl11b may negatively regulate this lineage. Using Nippostrongylus brasiliensis infection, we reveal that the absence of Bcl11b leads to impaired worm expulsion, caused by a deficit in ILC2s, whereas Citrobacter rodentium infection is cleared efficiently. These data clearly establish Bcl11b as a new factor in the differentiation of ILC2s.
The development and fate of follicular helper T cells defined by an IL-21 reporter mouse.
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.
CIS is a potent checkpoint in NK cell–mediated tumor immunity
Publisher: Springer Science and Business Media LLC
Date: 23-05-2016
DOI: 10.1038/NI.3470
Abstract: The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.
Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity
Publisher: Springer Science and Business Media LLC
Date: 23-08-2021
DOI: 10.1038/S41590-021-01004-1
Abstract: Tissue-resident memory T (T
Multiple dendritic cell populations activate CD4+ T cells after viral stimulation
Publisher: Public Library of Science (PLoS)
Date: 27-02-2008
Suppressor of Cytokine Signaling 4 (SOCS4) Protects against Severe Cytokine Storm and Enhances Viral Clearance during Influenza Infection
Publisher: Public Library of Science (PLoS)
Date: 08-05-2014
Mobilizing forces - CD4+ helper T cells script adaptive immunity
Publisher: Springer Science and Business Media LLC
Date: 2010
DOI: 10.1038/CR.2010.1
Life in the balance: killer T‐cell self‐control fends off lethal influenza?
Publisher: Wiley
Date: 14-04-2009
DOI: 10.1038/ICB.2009.22
A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
Publisher: Springer Science and Business Media LLC
Date: 26-09-2016
DOI: 10.1038/NI.3565
Abstract: Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
Intercellular and lymphatic pathways associated with tonsils of the soft palate in young pigs
Publisher: Springer Science and Business Media LLC
Date: 23-03-1998
Abstract: Tonsils of the soft palate of pigs are the main oropharyngeal lymphoid tissues that protect the body against antigens entering through the mouth. The aim of this work was to elucidate the intercellular and lymphatic pathways by which lymph and cells are transported through these tonsils. Tonsillar tissue from freshly-killed pigs was examined using light microscopy and electron microscopy, or was injected with Mercox for scanning electron microscopy of corrosion casts. Intercellular fluid passes between epithelial cells and is continuous with that of the subepithelium. Fluid from the subepithelium flows into sinuses that form a network around the apex of follicles. These sinuses are continuous with parafollicular sinuses that penetrate the parafollicular tissue between the follicles. Some parafollicular sinuses are traversed by a complex network of cell processes, whereas others appear to lack such processes. Some parafollicular sinuses are closely located (10 microm) to venules others lie adjacent to the follicle capsule. No lymphatics enter or leave the follicles. All lymph from the tonsils must traverse parafollicular sinuses before entering septal vessels, and these are continuous with basal vessels. Basal vessels coalesce to form efferent vessels that transport lymph from the tonsil to the primary lymph nodes. Septal, basal and efferent lymphatic vessels contain prominent valves and many lymphocytes. Lymphatic sinuses appear to be a significant pathway for lymphocytes migrating from the tonsillar lymphoid tissue.
Contrôle épigénétique de la stabilité phénotypique et fonctionnelle des lymphocytes Th2 par la voie Suv39h1/HP1α
Publisher: EDP Sciences
Date: 12-2012
Innate lymphoid cells and cancer
Publisher: Springer Science and Business Media LLC
Date: 28-02-2022
DOI: 10.1038/S41590-022-01127-Z
Abstract: The innate lymphoid cell (ILC) family is composed of natural killer (NK) cells, ILC1, ILC2 and ILC3, which participate in immune responses to virus, bacteria, parasites and transformed cells. ILC1, ILC2 and ILC3 subsets are mostly tissue-resident, and are profoundly imprinted by their organ of residence. They exhibit pleiotropic effects, driving seemingly paradoxical responses such as tissue repair and, alternatively, immunopathology toward allergens and promotion of tumorigenesis. Despite this, a trickle of studies now suggests that non-NK ILCs may not be overwhelmingly tumorigenic and could potentially be harnessed to drive anti-tumor responses. Here, we examine the pleiotropic behavior of ILCs in cancer and begin to unravel the gap in our knowledge that exposes a new horizon for thinking about modifying ILCs and targeting them for immunotherapy.
An investigation of the use of chromium, platinum and gold coating for scanning electron microscopy of casts of lymphoid tissues
Publisher: Elsevier BV
Date: 1995
DOI: 10.1016/0968-4328(95)00055-9
Abstract: Resin casts replicate the internal structure of organs and provide a three-dimensional representation of the arrangement of vessels and intercellular spaces. Casting media are insulators and must be coated with a conductor to prevent s le charging and to allow the adequate production of secondary electrons from the specimen to generate sufficient signal to form a clear image. Visualization of surface structures depends largely on the metal coating. The use of gold or platinum, deposited on Mercox casts of lymphoid tissues using plasma-magnetron sputtering, and of chromium coating of casts by Penning ion-beam coating, was investigated. Casts were examined using a field emission scanning electron microscope at 3-3.5 kV. Thick coatings of gold were necessary to reduce cast charging but they obscured fine structural information. Charging effects were less pronounced when casts were coated with platinum, but charge lines were present at slow scan rates. The dimensions of cast impressions for both platinum and chromium coatings were similar to those described in fixed tissues. Negligible charging and maximal cast thermal stability and structural information was obtained from casts which were tumbled during chromium coating.
Metabolic features of innate lymphoid cells
Publisher: Rockefeller University Press
Date: 27-10-2022
DOI: 10.1084/JEM.20221140
Abstract: Innate and adaptive immune cells are found in distinct tissue niches where they orchestrate immune responses. This requires intrinsic and temporal metabolic adaptability to coordinately activate the immune response cascade. Dysregulation of this program is a key feature of immunosuppression. Direct or indirect metabolic immune cell reprogramming may offer new approaches to modulate immune cells behavior for therapy to overcome dysregulation. In this review, we explored how metabolism regulates lymphocytes beyond the classical T cell subsets. We focus on the innate lymphoid cell (ILC) family, highlighting the distinct metabolic characteristics of these cells, the impact of environmental factors, and the receptors that could alter immune cell functions through manipulation of metabolic pathways to potentially prevent or treat various diseases.
The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells
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.
Spatial Profiling of Lung SARS-CoV-2 and Influenza Virus Infection Dissects Virus-Specific Host Responses and Gene Signatures
Publisher: Cold Spring Harbor Laboratory
Date: 06-11-2020
DOI: 10.1101/2020.11.04.20225557
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). Robust blood biomarkers that reflect tissue damage are urgently needed to better stratify and triage infected patients. Here, we use spatial transcriptomics to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19 (10 patients), pandemic H1N1 (pH1N1) influenza (5) and uninfected control patients (4). Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs with few areas of high viral load and these were largely only associated with an increased type I interferon response. A very limited number of genes were differentially expressed between the lungs of influenza and COVID-19 patients. Specific interferon-associated genes (including IFI27 ) were identified as candidate novel biomarkers for COVID-19 differentiating this COVID-19 from influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.
Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity.
Publisher: Wiley
Date: 14-06-2012
Abstract: The importance of costimulation on CD4(+) T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4(+) T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar naïve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44(+) BrdU(+) influenza-specific CD8(+) T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8(+) T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell ision. As shown previously, neither viral clearance nor the generation of influenza-specific CD8(+) T cells was affected by the absence of CD4(+) T cells alone. In contrast, both were markedly impaired by CD28 blockade of "helpless" CD8(+) T cells. We suggest that direct CD28 costimulation of CD8(+) T cells is more critical in their priming during primary influenza infection than previously appreciated.
The evolution of innate lymphoid cells
Publisher: Springer Science and Business Media LLC
Date: 21-06-2016
DOI: 10.1038/NI.3459
Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling
Publisher: eLife Sciences Publications, Ltd
Date: 14-02-2017
DOI: 10.7554/ELIFE.20444
Abstract: Influenza virus infections have a significant impact on global human health. In iduals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.
BH3-only protein Puma contributes to death of antigen-specific T cells during shutdown of an immune response to acute viral infection.
Publisher: Proceedings of the National Academy of Sciences
Date: 26-02-2008
Abstract: During acute T cell immune responses to viral infection, antigen-specific T cells first proliferate and differentiate into effector cells, but after pathogen clearance most are deleted by apoptosis. The developmentally programmed death of antigen-specific T cells during shutdown of a T cell response is mediated by the Bcl-2-regulated apoptotic pathway and partly depends on the proapoptotic BH3-only protein Bim. However, loss of Bim enhanced survival of antigen-activated T cells to a lesser extent than Bcl-2 overexpression, indicating that other proapoptotic factors must contribute to T cell killing. In this study, we investigated the contributions of several BH3-only proteins to the shutdown of an acute T cell immune response in vivo . After infection with human herpes simplex virus (HSV-1), mice lacking Noxa, Bid, or Bad had a normal increase and subsequent decline in the numbers of antigen-specific CD8 + T cells. In contrast, Puma-deficient mice showed an abnormally prolonged persistence of antigen-specific CD8 + T cells in the spleen, associated with enhanced in vitro survival of these cells in the absence of cytokines. Puma was dispensable for viral clearance and also did not play a role in proliferation or activation of HSV-1-specific CD8 + T cells in vivo . Collectively, these findings show that Puma contributes to the death of antigen-specific T cells during shutdown of an immune response.
Complementarity and redundancy of IL-22-producing innate lymphoid cells
Publisher: Springer Science and Business Media LLC
Date: 30-11-2015
DOI: 10.1038/NI.3332
Virus-specific CD8+ T cells in primary and secondary influenza pneumonia
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1016/S1074-7613(00)80573-7
Abstract: Virus-specific CD8+ effector T cells (eCTL) are enriched in the lungs of mice with primary influenza pneumonia, though later detection of memory T cells (mCTL) in the mediastinal lymph nodes (MLN) or spleen by peptide-based staining protocols is at the limits of flow cytometric analysis. Respiratory challenge with an H3N2 virus months after H1N1 priming induces a massive recall response, which reduces virus titers 2-3 days earlier than in nave controls. Influenza-specific mCTL produce interferon-gamma within 6 hr, but still take 4-5 days to localize to the infected respiratory tract. The delay reflects that the recall response develops first in the MLN, which contains relatively few mCTL. The response to a subdominant epitope is less obvious after secondary challenge.
ZBTB46 in ILC3: shared transcriptional infrastructure defines gut-protective capabilities
Publisher: Elsevier BV
Date: 09-2022
Abstract: Group 3 innate lymphoid cells (ILC3s) are distributed along the gastrointestinal tract at the interface between the immune system and the gut lumen, which carries a significant microbial burden. In a new study, Zhou et al. investigated the expression of transcription factor ZBTB46, normally thought to be restricted to classical dendritic cells (cDCs), and discovered that ZBTB46 expression by ILC3s in the mouse colon forms an essential part of the gastrointestinal armory to calibrate inflammatory responses.
Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells
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.
Measuring the diaspora for virus-specific CD8+T cells
Publisher: Proceedings of the National Academy of Sciences
Date: 08-05-2001
Abstract: The CD8 + T cell diaspora has been analyzed after secondary challenge with an influenza A virus that replicates only in the respiratory tract. Numbers of D b NP 366 - and D b PA 224 -specific CD8 + T cells were measured by tetramer staining at the end of the recall response, then followed sequentially in the lung, lymph nodes, spleen, blood, and other organs. The extent of clonal expansion did not reflect the sizes of the preexisting memory T cell pools. Although the high-frequency CD8 + tetramer + populations in the pneumonic lung and mediastinal lymph nodes fell rapidly from peak values, the “whole mouse” virus-specific CD8 + T cell counts decreased only 2-fold over the 4 weeks after infection, then subsided at a fairly steady rate to reach a plateau at about 2 months. The largest numbers were found throughout in the spleen, then the bone marrow. The CD8 + D b NP 366 + and CD8 + D b PA 224 + sets remained significantly enlarged for at least 4 months, declining at equivalent rates while retaining the nucleoprotein acid polymerase immunodominance hierarchy characteristic of the earlier antigen-driven phase. Lowest levels of the CD69 “activation marker” were detected consistently on virus-specific CD8 + T cells in the blood, then the spleen. Those in the bone marrow and liver were intermediate, and CD69 hi T cells were very prominent in the regional lymph nodes and the nasal-associated lymphoid tissue. Any population of “resting” CD8 + memory T cells is thus phenotypically heterogeneous, widely dispersed, and subject to broad homeostatic and local environmental effects irrespective of epitope specificity or magnitude.
A complementary role for the tetraspanins CD37 and Tssc6 in cellular immunity
Publisher: The American Association of Immunologists
Date: 15-09-2010
Abstract: The cooperative nature of tetraspanin–tetraspanin interactions in membrane organization suggests functional overlap is likely to be important in tetraspanin biology. Previous functional studies of the tetraspanins CD37 and Tssc6 in the immune system found that both CD37 and Tssc6 regulate T cell proliferative responses in vitro. CD37−/− mice also displayed a hyper-stimulatory dendritic cell phenotype and dysregulated humoral responses. In this study, we characterize “double knockout” mice (CD37−/−Tssc6−/−) generated to investigate functional overlap between these tetraspanins. Strong evidence for a cooperative role for these two proteins was identified in cellular immunity, where both in vitro T cell proliferative responses and dendritic cell stimulation capacity are significantly exaggerated in CD37−/−Tssc6−/− mice when compared with single knockout counterparts. Despite these exaggerated cellular responses in vitro, CD37−/−Tssc6−/− mice are not more susceptible to autoimmune induction. However, in vivo responses to pathogens appear poor in CD37−/−Tssc6−/− mice, which showed a reduced ability to produce influenza-specific T cells and displayed a rapid onset hyper-parasitemia when infected with Plasmodium yoelii. Therefore, in the absence of both CD37 and Tssc6, immune function is further altered when compared with CD37−/− or Tssc6−/− mice, demonstrating a complementary role for these two molecules in cellular immunity.
Assessment of Gene Function of Mouse Innate Lymphoid Cells for In Vivo Analysis Using Retroviral Transduction
Publisher: Springer New York
Date: 2019
DOI: 10.1007/978-1-4939-9145-7_14
Abstract: Retroviral transduction is commonly used to modulate gene expression and is a powerful approach to understand the role of a gene using gain- or loss-of-function strategies. Retroviral vectors can stably integrate non-viral genes into host genomes, providing long-term modulation of gene expression in infected cells and their progeny. Here we describe the generation of retroviral supernatants and the steps to efficiently transduce genes in innate lymphoid cell (ILC) progenitors for subsequent analysis of ILC populations in vivo.
Id2 represses E2A-mediated activation of IL-10 expression in T cells
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.
Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers
Publisher: Frontiers Media SA
Date: 29-10-2018
Type 2 innate lymphoid cells: a novel actor in anti-melanoma immunity
Publisher: Informa UK Limited
Date: 2021
The linear range for accurately quantifying antigen-specific T-cell frequencies by tetramer staining during natural immune responses.
Publisher: Wiley
Date: 11-04-2011
Type 1 innate lymphoid cell biology: Lessons learnt from natural killer cells
Publisher: Frontiers Media SA
Date: 12-10-2016
Blimp-1 Transcription Factor Is Required for the Differentiation of Effector CD8+ T Cells and Memory Responses
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.
Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders.
Publisher: Wiley
Date: 23-08-2021
DOI: 10.1111/ALL.14548
Differentiation and diversity of subsets in group 1 innate lymphoid cells
Publisher: Oxford University Press (OUP)
Date: 07-09-2015
Abstract: NK cells were first identified in 1975 and represent the prototypical group 1 innate lymphoid cell (ILC). More recently, the discovery of new members of the ILC family has highlighted the complexity of this innate lymphoid lineage. Importantly, it has been recognized that different subsets exist within the group 1 ILC, which have potential roles in mediating immune protection and immunosurveillance, and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the different group 1 ILC, which have been identified to date and discuss how heterogeneity within this expanding family may have arisen.
Bid and Bim collaborate during induction of T cell death in persistent infection
Publisher: The American Association of Immunologists
Date: 04-2011
Abstract: Upon Ag encounter, naive T cells undergo extensive Ag-driven proliferation and can differentiate into effector cells. Up to 95% of these cells die leaving a small residual population of T cells that provide protective memory. In this study, we investigated the contribution of the BH3-only family protein Bid in the shutdown of T cell responses after acute and persistent infection. Influenza virus pathogenicity has been proposed to be mediated by a peptide encoded in the basic polymerase (PB1-RF2) acting through Bid. In our experiments, we found that after acute infection with influenza virus, mice lacking Bid had normal expansion and contraction of Ag-specific CD8+ T cells. However, in chronic γ-herpesvirus infection, Bid-deficient virus-specific CD8+ T cells expanded normally but failed to contract fully and were maintained at ∼2-fold higher levels. Previously, we have demonstrated that Bim plays a prominent role in T cell shutdown in persistent infection by cooperating with the death receptor Fas, which regulates apoptosis in response to repeated TCR signaling. Bid lies at the nexus of these two signaling pathways, thus we reasoned that Bid and Bim might cooperate in regulation of T cell shutdown in persistent infection. In this study, we observed that the combined loss of Bid and Bim synergistically enhanced the persistence of CD8+ T cells during γ-herpesvirus infection. Thus, these data uncover a role for Bid in coordinating apoptotic signaling pathways to ensure appropriate shutdown of T cell immune responses in the setting of persistent Ag exposure.
Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance
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.
Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism.
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.
Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection.
Publisher: Elsevier BV
Date: 08-2019
Most lymphoid organ dendritic cell types are phenotypically and functionally immature
Publisher: American Society of Hematology
Date: 15-09-2003
DOI: 10.1182/BLOOD-2003-02-0513
Abstract: Dendritic cells (DCs) have been thought to follow a life history, typified by Langerhans cells (LCs), with 2 major developmental stages: an immature stage that captures antigens in the periphery and a mature stage that presents those antigens in the lymphoid organs. However, a systematic assessment of the maturity of lymphoid organ DCs has been lacking. We have analyzed the maturity of the DC types found in the steady state in the spleen, lymph nodes (LNs), and thymus. The DCs that migrate into the iliac, mesenteric, mediastinal, or subcutaneous LNs from peripheral tissues were mature and therefore could not process and present newly encountered antigens. However, all the other DC types were phenotypically and functionally immature: they expressed low levels of surface major histocompatibility complex class II (MHC II) and CD86, accumulated MHC II in their endosomes, and could present newly encountered antigens. These immature DCs could be induced to mature by culture in vitro or by inoculation of inflammatory stimuli in vivo. Therefore, the lymphoid organs contain a large cohort of immature DCs, most likely for the maintenance of peripheral tolerance, which can respond to infections reaching those organs and mature in situ.
Perforin and Fas in murine gammaherpesvirus-specific CD8+ T cell control and morbidity
Publisher: Microbiology Society
Date: 08-2001
DOI: 10.1099/0022-1317-82-8-1971
Abstract: The immune system uses both virus-specific T cells and B cells to control the acute and latent phases of respiratory infection with the murine gammaherpesvirus 68 (γHV-68). We sought to further define the important effector mechanisms for CD8 + T cells. First, depletion of the CD4 + T cells resulted in a failure of most animals to drive the virus into latency, although lytic virus in the lung was reduced by approximately 1000-fold from its peak. Second, the absence of either perforin or Fas alone had no impact on the ability to reduce titres of lytic virus in the lung. Further neutralization of IFN-γ in CD4-depleted P +/+ , P −/− or Fas −/− mice had no effect. To define the requirements for Fas or perforin more clearly, two sets of chimeric mice were constructed differing in perforin expression by the T cells, and Fas on infected epithelial cells or lymphocytes. Animals with P −/− T cells and a Fas −/− lung failed to limit the shedding of infectious virus, regardless of whether CD4 T cells were present. In addition, we noted that having P −/− T cells in irradiated Fas +/+ hosts caused a lethal disease that was not apparent in the non-chimeric (unirradiated) P −/− (Fas +/+ ) mice. In another set of chimeric mice, P −/− T cells were able to limit persistent infection of B cells that expressed Fas, but not B cells that were Fas-deficient. These studies demonstrate that some degree of cytotoxicity via either perforin or Fas is essential for CD8 + T cells to control this DNA virus.
The Role of Antigen in the Localization of Naive, Acutely Activated, and Memory CD8+ T Cells to the Lung During Influenza Pneumonia
Publisher: The American Association of Immunologists
Date: 15-12-2001
DOI: 10.4049/JIMMUNOL.167.12.6983
Abstract: The role of Ag in the recruitment and localization of naive, acutely activated, and memory CD8+ T cells to the lung during influenza infection was explored using TCR-transgenic (Tg) mice. Naive, Thy1.2+CD8+ OT-I TCR-Tg cells were primed and recruited to the lung after transfer into congenic Thy1.1+ recipients challenged with a genetically engineered influenza virus (influenza A/WSN/33 (WSN)-OVAI) containing the Kb restricted OVA257–264 epitope (siinfekl) in the viral neuraminidase stalk. However, if the transferred animals were infected with a similar influenza virus that expressed an irrelevant Kb epitope (WSN-PEPII), no TCR-Tg T cells were detectable in the lung, although they were easily visible in the lymphoid organs. Conversely, there were substantial numbers of OT-I cells found in the lungs of WSN-PEPII-infected mice when the animals had been previously, or were concurrently, infected with a recombinant vaccinia virus expressing OVA. Similar results were obtained with nontransgenic populations of memory CD8+ T cells reactive to a murine γ-herpesvirus-68 Ag. Interestingly, the primary host response to the immunodominant influenza nucleoprotein epitope was not affected by the presence of memory or recently activated OT-I T cells. Thus, although Ag is required to activate the T cells, the subsequent localization of T cells to the lung during a virus infection is a property of recently activated and memory T cells and is not necessarily driven by Ag in the lung.
TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-10-2023
Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice.
Publisher: Rockefeller University Press
Date: 25-10-2004
DOI: 10.1084/JEM.20041328
Abstract: Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7Rα chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7Rα–deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7Rα double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7Rα−/− mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7–deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients.
The tapestry of the immune response for protective immunity
Publisher: Informa UK Limited
Date: 02-2009
DOI: 10.4161/HV.5.2.7841
A divergent transcriptional landscape underpins the development and functional branching of MAIT cells
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-2019
DOI: 10.1126/SCIIMMUNOL.AAY6039
Abstract: Characterizing MAIT cell development led to the identification of key regulators that specify MAIT cell fate in the thymus.
Vasoactive intestinal peptide confers anticipatory mucosal immunity by regulating ILC3 activity
Publisher: Cold Spring Harbor Laboratory
Date: 08-08-2019
DOI: 10.1101/729400
Abstract: ILC3-mediated IL-22 cytokine production is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we show that group 3 ILC (ILC3) constitutive function is not constant across the day but instead oscilliates between active and resting phases. Coordinate responsiveness of ILC3 in the intestine depended on food-induced expression of the neuronal hormone vasoactive intestinal peptide (VIP). Intestinal ILC3 expressed high levels of the G protein-coupled receptor, VIPR2, and activation via enteric neuronal VIP markedly enhanced IL-22 production and conferred gut protection. Conversely, deficiency of VIPR2 signalling led to impaired production of IL-22 by ILC3 and increased susceptibility to inflammatory gut disease. As such, intrinsic cellular rhythms synergise with the cyclic patterns of food intake to drive IL-22 thereby syncronizing intestinal epithelial protection via the ILC3 VIP-VIPR2 pathway.
Androgen signaling negatively controls group 2 innate lymphoid cells
Publisher: Rockefeller University Press
Date: 08-05-2017
DOI: 10.1084/JEM.20161807
Abstract: Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33–driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33–mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33–driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.
Intestinal-derived ILCs migrating in lymph increase IFNγ production in response to Salmonella Typhimurium infection
Publisher: Elsevier BV
Date: 05-2021
Transcription Factor T-bet in B Cells Modulates Germinal Center Polarization and Antibody Affinity Maturation in Response to Malaria.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.CELREP.2019.10.087
Abstract: Despite the key role that antibodies play in protection, the cellular processes mediating the acquisition of humoral immunity against malaria are not fully understood. Using an infection model of severe malaria, we find that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. Molecular and cellular analyses reveal that T-bet in B cells is required not only for IgG
The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens.
Publisher: Rockefeller University Press
Date: 14-10-2002
DOI: 10.1084/JEM.20020861
Abstract: We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow–derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8α+ dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced β-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c+CD8α+ cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8α+ DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.
The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity
Publisher: Springer Science and Business Media LLC
Date: 23-12-2020
DOI: 10.1038/S41590-019-0567-Y
Abstract: Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP-VIPR2 pathway in ILC3s.
Absence of Batf3 reveals a new dimension of cell state heterogeneity within conventional dendritic cells
Publisher: Elsevier BV
Date: 05-2021
The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells.
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.
Innate Lymphoid Cells Type 3
Publisher: Elsevier
Date: 2016
Immunology and Cell Biology Publication of the Year Awards 2013
Publisher: Wiley
Date: 11-2014
DOI: 10.1038/ICB.2014.92
Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513609.V1
Abstract: Abstract The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4 sup + /sup and CD8 sup + /sup T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. Significance: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer. /
Eomesodermin promotes the development of type 1 regulatory T (T R 1) cells
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-04-2017
DOI: 10.1126/SCIIMMUNOL.AAH7152
Abstract: T R 1 cells are the major regulatory population generated after allogeneic bone marrow transplantation.
Cross‐presentation, dendritic cell subsets, and the generation of immunity to cellular antigens
Publisher: Wiley
Date: 05-05-2004
Therapeutic ISCOMATRIX™ adjuvant vaccine elicits effective anti-tumor immunity in the TRAMP-C1 mouse model of prostate cancer
Publisher: Springer Science and Business Media LLC
Date: 09-05-2020
Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells
Publisher: Springer Science and Business Media LLC
Date: 31-07-2017
DOI: 10.1038/NI.3800
Abstract: Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49a
A previously unrecognized H-2Db-restricted peptide prominent in the primary influenza a virus-specific CD8+ T-cell response is much less apparent following secondary challenge
Publisher: American Society for Microbiology
Date: 15-04-2000
DOI: 10.1128/JVI.74.8.3486-3493.2000
Abstract: Respiratory challenge of H-2 b mice with an H3N2 influenza A virus causes an acute, transient pneumonitis characterized by the massive infiltration of CD8 + T lymphocytes. The inflammatory process monitored by quantitative analysis of lymphocyte populations recovered by bronchoalveolar lavage is greatly enhanced by prior exposure to an H1N1 virus, with the recall of cross-reactive CD8 + -T-cell memory leading to more rapid clearance of the infection from the lungs. The predominant epitope recognized by the influenza virus-specific CD8 + set has long been thought to be a nucleoprotein (NP 366–374 ) presented by H-2D b (D b NP 366 ). This continues to be true for the secondary H3N2→H1N1 challenge but can no longer be considered the case for the primary response to either virus. Quantitative analysis based on intracellular staining for gamma interferon has shown that the polymerase 2 protein (PA 224–233 ) provides a previously undetected epitope (D b PA 224 ) that is at least as prominent as D b NP 366 during the first 10 days following primary exposure to either the H3N2 or H1N1 virus. The response to D b NP 366 seems to continue for longer, even when infectious virus can no longer be detected, but there is no obvious difference in the prevalence of memory T cells specific for D b NP 366 and D b PA 224 . The generalization that the magnitude of the functional memory T-cell pool is a direct consequence of the clonal burst size during the primary response may no longer be useful. Previous CD8 + -T-cell immunodominance heirarchies defined largely by cytotoxic T-lymphocyte assays may need to be revised.
Activated mouse B cells lack expression of granzyme B.
Publisher: The American Association of Immunologists
Date: 15-04-2012
Abstract: Recently, it has been reported that human B cells express and secrete the cytotoxic protease granzyme B (GrB) after stimulation with IL-21 and BCR cross-linking. To date, there are few clues on the function of GrB in B cell biology. As experimental transgenic murine systems should provide insights into these issues, we assayed for GrB in C57BL/6 B cells using an extensive array of physiologically relevant stimuli but were unable to detect either GrB expression or its proteolytic activity, even when Ag-specific transgenic BCRs were engaged. Similar results were also obtained with B cells from DBA/2, CBA, or BALB/c mice. In vivo, infection with either influenza virus or murine γ-herpesvirus induced the expected expression of GrB in CTLs, but not in B cell populations. We also investigated a possible role of GrB on the humoral immune response to the model Ag 4-hydroxy-3-nitrophenylacetyl–keyhole limpet hemocyanin, but GrB-deficient mice produced normal amounts of Ab with typical affinity maturation and a heightened secondary response, demonstrating conclusively the redundancy of GrB for Ab responses. Our results highlight the complex evolutionary differences that have shaped the immune systems of mice and humans. The physiological consequences of GrB expression in human B cells remain unclear, and the current study suggests that experimental mouse models will not be helpful in addressing this issue.
A γ-herpesvirus sneaks through a CD8+T cell response primed to a lytic-phase epitope
Publisher: Proceedings of the National Academy of Sciences
Date: 03-08-1999
Abstract: To determine whether established CD8 + T cell memory to an epitope prominent during the replicative phase of a γ-herpesvirus infection protects against subsequent challenge, mice were primed with a recombinant vaccinia virus expressing the p56 peptide and then boosted by intranasal exposure to an influenza A virus incorporating p56 in the neuraminidase protein. Clonally expanded populations of functional, p56-specific CD8 + T cells were present at high frequency in both the lung and the lymphoid tissue 1 month later, immediately before respiratory challenge with γHV-68. This prime-and-boost regime led to a massive reduction of productive γHV-68 infection in the respiratory tract and, initially, to much lower levels of latency in both the regional lymph nodes and the spleen. The CD8 + T cell response to another epitope (p79) was diminished, there was less evidence of B cell activation, and the onset of the CD4 + T cell-dependent splenomegaly was delayed. Within 3–4 weeks of the γHV-68 challenge, however, the extent of latent infection in the lymph nodes and spleen was equivalent, and both groups developed the prominent infectious mononucleosis-like syndrome that is characteristic of this infection. The reverse protocol (influenza then vaccinia) seemed to be slightly less effective. Even though immune CD8 + T cells may be present at the time and site of virus challenge, establishing a high level of CD8 + T cell memory to lytic-phase epitopes alone does not protect against the longer-term consequences of this γHV infection.
Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity
Publisher: Springer Science and Business Media LLC
Date: 15-01-2006
DOI: 10.1038/NI1300
Abstract: The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.
Diverse roles of inhibitor of differentiation 2 in adaptive immunity.
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/281569
Abstract: The helix-loop-helix (HLH) transcription factor inhibitor of DNA binding 2 (Id2) has been implicated as a regulator of hematopoiesis and embryonic development. While its role in early lymphopoiesis has been well characterized, new roles in adaptive immune responses have recently been uncovered opening exciting new directions for investigation. In the innate immune system, Id2 is required for the development of mature natural killer (NK) cells, lymphoid tissue-inducer (LTi) cells, and the recently identified interleukin (IL)-22 secreting nonconventional innate lymphocytes found in the gut. In addition, Id2 has been implicated in the development of specific dendritic cell (DC) subsets, decisions determining the formation of αβ and γδ T-cell development, NK T-cell behaviour, and in the maintenance of effector and memory CD8 + T cells in peripheral tissues. Here, we review the current understanding of the role of Id2 in lymphopoiesis and in the development of the adaptive immune response required for maintaining immune homeostasis and immune protection.
IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1038/MI.2013.122
Abstract: Natural killer T (NKT) cells are innate-like T cells that rapidly recognize pathogens and produce cytokines that shape the ensuing immune response. IL-17-producing NKT cells are enriched in barrier tissues, such as the lung, skin, and peripheral lymph nodes, and the factors that maintain this population in the periphery have not been elucidated. Here we show that NKT17 cells deviate from other NKT cells in their survival requirements. In contrast to conventional NKT cells that are maintained by IL-15, RORγt(+) NKT cells are IL-15 independent and instead rely completely on IL-7. IL-7 initiates a T-cell receptor-independent (TCR-independent) expansion of NKT17 cells, thus supporting their homeostasis. Without IL-7, survival is dramatically impaired, yet residual cells remain lineage committed with no downregulation of RORγt evident. Their preferential response to IL-7 does not reflect enhanced signaling through STAT proteins, but instead is modulated via the PI3K/AKT/mTOR signaling pathway. The ability to compete for IL-7 is dependent on high-density IL-7 receptor expression, which would promote uptake of low levels of IL-7 produced in the non-lymphoid sites of lung and skin. This dependence on IL-7 is also reported for RORγt(+) innate lymphoid cells and CD4(+) Th17 cells, and suggests common survival requirements for functionally similar cells.
Innate lymphoid cells: parallel checkpoints and coordinate interactions with T cells
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.COI.2015.11.008
Abstract: Protection of epithelial and mucosal surfaces is required for survival. The recent discovery of a erse array of innate lymphoid cells that lie immediately beneath these surfaces has unexpectedly uncovered an entire defense system distinct from the adaptive system essential to protect these barriers. This multilayered design provides a robust system through coupling of two highly complementary networks to ensure immune protection. Here, we discuss the similarities in the hardwiring and ersification of innate lymphoid cells and T cells during mammalian immune responses.
Characteristics of virus-specific CD8+ T cells in the liver during the control and resolution phases of influenza pneumonia
Publisher: Proceedings of the National Academy of Sciences
Date: 10-11-1998
Abstract: Dissection of the primary and secondary response to an influenza A virus established that the liver contains a substantial population of CD8 + T cells specific for the immunodominant epitope formed by H-2D b and the influenza virus nucleoprotein peptide fragment NP 366–374 (DbNP366). The numbers of CD8 + DbNP366 + cells in the liver reflected the magnitude of the inflammatory process in the pneumonic lung, though replication of this influenza virus is limited to the respiratory tract. Analysis of surface phenotypes indicated that the liver CD8 + DbNP366 + cells tended to be more “activated” than the set recovered from lymphoid tissue but generally less so than those from the lung. The distinguishing characteristic of the lymphocytes from the liver was that the prevalence of the CD8 + DbNP366 + set was always much higher than the percentage of CD8 + T cells that could be induced to synthesize interferon γ after short-term, in vitro stimulation with the NP 366–374 peptide, whereas these values were generally comparable for virus-specific CD8 + T cells recovered from other tissue sites. Also, the numbers of apoptotic CD8 + T cells were higher in the liver. The results overall are consistent with the idea that antigen-specific CD8 + T cells are destroyed in the liver during the control and resolution phases of this viral infection, though this destruction is not necessarily an immediate process.
Natural killer cells and anti-tumor immunity
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.MOLIMM.2017.12.002
Abstract: Immune checkpoint inhibitors harness the power of the immune system to fight cancer. The clinical success achieved with antibodies against the inhibitory T cell receptors PD-1 and CTLA4 has focused attention on the possibility of manipulating other immune cells, in particular those involved in innate immunity. Here we review the role of innate lymphoid cells (ILCs) and their contribution to tumor immunity. As the prototypical ILC, the natural killer (NK) cell has an intrinsic ability to detect and kill cancer cells. NK cells are dependent on the cytokine interleukin (IL)-15 for their development and effector activity. We discuss the role of the Suppressor of cytokine (SOCS) proteins in negatively regulating IL-15 and NK cell responses and the potential for targeting these small intracellular regulators as new immune checkpoints.
SOCS4 is dispensable for an efficient recall response to influenza despite being required for primary immunity
Publisher: Wiley
Date: 16-06-2015
DOI: 10.1038/ICB.2015.55
Abstract: Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. Mice lacking functional SOCS4 are hypersusceptible to primary infection with influenza A virus (IAV), displaying dysregulated pro-inflammatory cytokine and chemokine production in the lungs, delayed viral clearance and impaired trafficking of influenza-specific CD8(+) T cells to the site of infection. Therefore, we postulated that SOCS4 is a critical regulator of anti-viral immunity. Unexpectedly, SOCS4 was not required for CD8(+) T-cell memory generation, nor was it required to efficiently recall those cells in response to secondary IAV infection. Wild-type or SOCS4-deficient mice primed and re-challenged with serologically different influenza strains, did not show differences in susceptibility to IAV and cleared the virus from the lungs at the same rate. We have not observed differences in trafficking or numbers of IAV-specific cells, numbers of resident memory T cells or in cytokine profiles in lungs of infected animals. Our data show that despite an impaired primary immune response in Socs4(R108X/R108X) mice, SOCS4 is dispensable for an efficient recall response to influenza virus infection.
Neuroimmune Interactions and Rhythmic Regulation of Innate Lymphoid Cells
Publisher: Frontiers Media SA
Date: 29-04-2021
DOI: 10.3389/FNINS.2021.657081
Abstract: The Earth’s rotation around its axis, is one of the parameters that never changed since life emerged. Therefore, most of the organisms from the cyanobacteria to humans have conserved natural oscillations to regulate their physiology. These daily oscillations define the circadian rhythms that set the biological clock for almost all physiological processes of an organism. They allow the organisms to anticipate and respond behaviorally and physiologically to changes imposed by the day/night cycle. As other physiological systems, the immune system is also regulated by circadian rhythms and while diurnal variation in host immune responses to lethal infection have been observed for many decades, the underlying mechanisms that affect immune function and health have only just started to emerge. These oscillations are generated by the central clock in our brain, but neuroendocrine signals allow the synchronization of the clocks in peripheral tissues. In this review, we discuss how the neuroimmune interactions create a rhythmic activity of the innate lymphoid cells. We highlight how the disruption of these rhythmic regulations of immune cells can disturb homeostasis and lead to the development of chronic inflammation in murine models.
Killer T cells regulate antigen presentation for early expansion of memory, but not naive, CD8+ T cell
Publisher: Proceedings of the National Academy of Sciences
Date: 10-04-2007
Abstract: Antigen presentation within the lymph node draining a site of infection is crucial for initiation of cytotoxic T cell responses. Precisely how this antigen presentation regulates T cell expansion in vivo is unclear. Here, we show that, in primary infection, antigen presentation peaks ≈3 days postinfection and then slowly decays until day 12. This prolonged antigen presentation is required for optimal expansion of naive CD8 + T cells, because early ablation of dendritic cells reduces the later CD8 + T cell response. Antigen presentation during secondary infection was 10-fold lower in magnitude and largely terminated by day 4 postinfection. Expansion of memory, but not naive, antigen-specific T cells was tightly controlled by perforin-dependent cytolysis of antigen-presenting cells. The ability of the memory T cells to remove antigen-presenting cells provides a negative-feedback loop to directly limit the duration of antigen presentation in vivo .
Bone marrow-derived cells expand memory CD8+ T cells in response to viral infections of the lung and skin
Publisher: Wiley
Date: 02-2006
Abstract: While naive CD8(+) T cells have been shown to require bone marrow-derived dendritic cells (DC) to initiate immunity, such a requirement for memory CD8(+) T cells has had limited assessment. By generating bone marrow chimeras that express the appropriate antigen-presenting molecules on either radiation-sensitive bone marrow-derived or radiation-resistant non-bone marrow-derived compartments, we showed that both primary and secondary immune responses to influenza virus infection of the lung were initiated in the draining LN. This required cells of bone marrow origin, most likely DC, for optimal expansion within the secondary lymphoid compartment. This was similarly the case with HSV-1 infection of the skin. As Langerhans cells are radioresistant, unlike other DC populations, these studies also demonstrate that the radiosensitive DC responsible for secondary expansion of HSV-specific memory are not Langerhans cells.
NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology
Publisher: BMJ
Date: 14-12-2019
DOI: 10.1136/ANNRHEUMDIS-2018-213764
Abstract: NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans. Here, we characterised a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry. Parallel studies were performed in a mouse model. The patients inherited a novel p.M170I in NFIL3 from each of the parents. The mutant form of NFIL3 demonstrated reduced stability in vitro. The potential contribution of this mutation to arthritis susceptibility was demonstrated through a preclinical model, where Nfil3-deficient mice upregulated IL-1β production, with more severe arthritis symptoms on disease induction. Single cell sequencing of patient blood quantified the transcriptional dysfunctions present across the peripheral immune system, converging on IL-1β as a pivotal cytokine. NFIL3 mutation can sensitise for arthritis development, in mice and humans, and rewires the innate immune system for IL-1β over-production.
Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives
Publisher: MDPI AG
Date: 22-08-2021
DOI: 10.3390/IJMS22169044
Abstract: Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) are specific innate lymphoid cell subsets that are key for the detection and elimination of pathogens and cancer cells. In liver, while they share a number of characteristics, they differ in many features. These include their developmental pathways, tissue distribution, phenotype and functions. NK cells and ILC1 contribute to organ homeostasis through the production of key cytokines and chemokines and the elimination of potential harmful bacteria and viruses. In addition, they are equipped with a wide range of receptors, allowing them to detect “stressed cells’ such as cancer cells. Our understanding of the role of innate lymphoid cells in hepatocellular carcinoma (HCC) is growing owing to the development of mouse models, the progress in immunotherapeutic treatment and the recent use of scRNA sequencing analyses. In this review, we summarize the current understanding of NK cells and ILC1 in hepatocellular carcinoma and discuss future strategies to take advantage of these innate immune cells in anti-tumor immunity. Immunotherapies hold great promise in HCC, and a better understanding of the role and function of NK cells and ILC1 in liver cancer could pave the way for new NK cell and/or ILC1-targeted treatment.
Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance
Publisher: Proceedings of the National Academy of Sciences
Date: 10-03-2009
Abstract: Autoimmune diseases tend to be chronic and progressive, but how these responses are sustained is not clear. One cell type that might contribute to autoimmunity is the cytotoxic T lymphocyte (CTL), which, as a consequence of causing tissue destruction and production of cytokines, could provide a sustained supply of antigen and inflammatory signals for dendritic cells to maintain immune stimulation. Here we examined whether such CTL-mediated tissue damage alone could provide antigen in the right context to recruit immune effectors and sustain autoimmunity. We show that while CTL-mediated tissue damage caused the release of self-antigens that stimulated the proliferation of naive autoreactive CD8 + T cells, such responses failed to precipitate disease and, instead, led to deletional tolerance. These findings indicate that despite the capacity of CTLs to produce inflammatory cytokines and to cause tissue damage, their responses are not sustaining, but instead favor induction of self-tolerance.
A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets
Publisher: Informa UK Limited
Date: 15-08-2018
Related Organisations
Walter And Eliza Hall Institute Of Medical Research
Location: Australia
Related Funding Activities
ARC Future Fellowships - Grant ID: FT110100283
Start Date: 11-2012
End Date: 11-2016
Amount: $930,168.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP200101058
Start Date: 2020
End Date: 06-2023
Amount: $500,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP0212057
Start Date: 04-2002
End Date: 12-2002
Amount: $465,483.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP190101851
Start Date: 06-2019
End Date: 12-2023
Amount: $538,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP230101156
Start Date: 07-2023
End Date: 06-2026
Amount: $702,705.00
Funder: Australian Research Council
View Funded Activity