ORCID Profile
0000-0002-9271-0004
Current Organisations
UNSW Sydney
,
Garvan Institute of Medical Research
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.
Publisher: Wiley
Date: 05-2017
DOI: 10.1038/CTI.2017.17
Publisher: Wiley
Date: 10-2005
Abstract: Isotype switching by B cells is highly regulated by a group of cytokines including IL-4, IFN-gamma and TGF-beta. A B cell can only express one isotype at a time however, during an immune response it may be exposed to combinations of stimuli that provide it with conflicting switching instructions. To determine how such cytokine-induced isotype switch conflicts would be resolved, the responses of B cells exposed to multiple cytokines were investigated. To eliminate complications arising from simultaneous effects of switching cytokines on proliferation, ision number was used as a reference framework to monitor switching rate. The results show a clear hierarchy in which IFN-gamma is dominant over IL-4, and both IL-4 and IFN-gamma are dominant over TGF-beta. These studies reveal how B cells possess a set of logical decision criteria for dealing with pathogens that invoke a range of different stimuli.
Publisher: Wiley
Date: 03-2010
Abstract: Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCtheta results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-kappaB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-kappaB act downstream of PKCtheta to alter CD8(+) T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-kappaB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCtheta-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCtheta-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-kappaB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCtheta in controlling CD8(+) T-cell anergy induction.
Publisher: Rockefeller University Press
Date: 05-06-2023
DOI: 10.1084/JEM.20221105
Abstract: B cells develop from hematopoietic stem cells in the bone marrow. Once generated, they serve multiple roles in immune regulation and host defense. However, their most important function is producing antibodies (Ab) that efficiently clear invading pathogens. This is achieved by generating memory B cells that rapidly respond to subsequent Ag exposure, and plasma cells (PCs) that continually secrete Ab. These B cell subsets maintain humoral immunity and host protection against recurrent infections for extended periods of time. Thus, the generation of antigen (Ag)-specific memory cells and PCs underlies long-lived serological immunity, contributing to the success of most vaccines. Our understanding of immunity is often derived from animal models. However, analysis of in iduals with monogenic defects that disrupt immune cell function are unprecedented models to link genotypes to clinical phenotypes, establish mechanisms of disease pathogenesis, and elucidate critical pathways for immune cell development and differentiation. Here, we review fundamental breakthroughs in unraveling the complexities of humoral immunity in humans that have come from the discovery of inborn errors disrupting B cell function.
Publisher: Elsevier BV
Date: 08-2010
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.COI.2010.10.007
Abstract: CD4+ T cells can differentiate into numerous subsets characterized by expression of a suite of cytokines and effector molecules that endow them with specialized functions. By mediating the differentiation of B cells into memory and plasma cells following exposure to T-dependent antigens (Ag), T follicular helper (TFH) cells have emerged as the predominant subset of CD4+ T cells responsible for regulating humoral immunity. The generation of TFH cells from naïve precursors typically involves sequential cognate interactions with distinct populations of Ag-presenting cells (APCs): dendritic cells within the T-cell zone of lymphoid tissues, and activated B cells at the border of the T-zone and follicle, and then within a germinal center. Recent studies have illuminated the key roles of APCs in TFH development, and have also re-defined the role of B cells in this process.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-09-2014
Abstract: During an infection, T cells ide extensively and secrete proteins that can severely damage tissues. But T cells know when to stop—they express proteins on their surface such as CTLA4, which put on the brakes. Kuehn et al. now report genetic evidence of the importance of CTLA4 in humans (see the Perspective by Rieux-Laucat and Casanova). They identified six patients with mutations in one copy of CTLA4 . Patients presented with symptoms of an overzealous immune response, with immune cells infiltrating their organs. The findings support the idea that CTLA4 tells the immune system when enough is enough. Science , this issue p. 1623 see also p. 1560
Publisher: Cold Spring Harbor Laboratory
Date: 02-2022
DOI: 10.1101/2022.01.30.478400
Abstract: Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored erse polyclonal SARS-CoV- 2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. More naïve interferon-activated CD4 + T cells were recruited into the memory compartment and recovery was associated with the development of robust CD4 + memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection. Children have erse polyclonal SARS-CoV-2-specific naïve T cells Adults have clonally expanded exhausted SARS-CoV-2-specific memory T cells Interferon-activated naïve T cells differentiate into memory T cells in adults but not children Adults but not children develop robust memory T cell responses to SARS-CoV-2
Publisher: Springer Science and Business Media LLC
Date: 30-04-2021
Publisher: Springer Science and Business Media LLC
Date: 20-08-2018
Publisher: The American Association of Immunologists
Date: 15-09-2017
Abstract: Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of in iduals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such in iduals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation.
Publisher: Wiley
Date: 30-01-2012
DOI: 10.1111/J.1749-6632.2011.06361.X
Abstract: Regulated interactions between cells of the immune system facilitate the generation of successful immune responses, thereby enabling efficient neutralization and clearance of pathogens and the establishment of both cell- and humoral-mediated immunological memory. The corollary of this is that impediments to efficient cell-cell interactions, normally necessary for differentiation and effector functions of immune cells, underly the clinical features and disease pathogenesis of primary immunodeficiencies. In affected in iduals, these defects manifest as impaired long-term humoral immunity and susceptibility to infection by specific pathogens. In this review, we discuss the importance of, and requirements for, effective interactions between B cells and T cells during the formation of CD4(+) T follicular helper cells and the elicitation of cytotoxic function of virus-specific CD8(+) T cells, as well as how these processes are abrogated in primary immunodeficiencies due to loss-of-function mutations in defined genes.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2013
DOI: 10.1038/NI.2771
Publisher: Wiley
Date: 08-06-2010
DOI: 10.1038/ICB.2010.73
Publisher: Springer-Verlag
Date: 2005
Publisher: Springer Science and Business Media LLC
Date: 19-06-2020
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.JACI.2022.04.011
Abstract: Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown. This study sought to delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells. STAT activation was assessed by phospho-flow cytometry cell sorting. Differential gene expression was determined by RNA-sequencing and quantitative PCR. The requirement for STAT5B in B-cell and CD4 IL-21 activated STAT5 and strongly induced SOCS3 in human naive, but not memory, B cells. Deletion of STAT5B in B-cell lines diminished IL-21-mediated SOCS3 induction. PBMCs from STAT5B-null in iduals contained expanded populations of immunoglobulin class-switched B cells, CD21 These findings reveal novel roles for STAT5B in regulating IL-21-induced human B-cell differentiation. This is achieved by inducing SOCS3 to attenuate IL-21 signaling, and BCL6 to repress class switching and plasma cell generation. Thus, STAT5B is critical for restraining IL-21-mediated B-cell differentiation. These findings provide insights into mechanisms underpinning B-cell responses during primary and subsequent antigen encounter and explain autoimmunity and dysfunctional humoral immunity in STAT5B deficiency.
Publisher: Wiley
Date: 05-2017
DOI: 10.1038/CTI.2017.26
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-06-2018
DOI: 10.1126/SCIIMMUNOL.AAT4956
Abstract: ZNF341 is a newly characterized transcription factor controlling baseline and inducible transcription of the human STAT3 gene.
Publisher: Rockefeller University Press
Date: 11-11-2013
DOI: 10.1084/JEM.20130323
Abstract: Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5 ERK PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in erse tissues, including in in idual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications.
Publisher: American Society for Clinical Investigation
Date: 03-10-2022
DOI: 10.1172/JCI160929
Publisher: Wiley
Date: 24-06-2022
DOI: 10.1111/IMCB.12565
Abstract: Researchers have identified a new monogenic form of systemic lupus erythematosus caused by mutations that result in increased Toll-like receptor 7 (TLR7) signaling.
Publisher: Wiley
Date: 28-01-2022
DOI: 10.1111/IMR.13067
Abstract: Better treatment of autoimmune diseases requires an improved understanding of the cellular and molecular mechanisms that lead to the breakdown of immune tolerance. The discovery of in iduals with germline mutations in PIK3CD (which encodes the p110δ catalytic subunit of PI3K) has revealed the importance of regulated PI3Kδ activity to maintain tolerance. These patients display a range of symptoms including both immunodeficiency and autoimmunity. Here, we discuss recent advances in our understanding of how dysregulated PI3Kδ signaling affects the activation and differentiation of multiple cell types leading to the production of autoantibodies in these patients. This has lessons, not only for the treatment of these patients, but also for the potential role of dysregulated PI3Kδ in other patients with autoimmune conditions.
Publisher: American Society for Clinical Investigation
Date: 17-04-2017
DOI: 10.1172/JCI90727
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.IMMUNI.2015.03.002
Abstract: B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169(+) subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen-experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen.
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.
Publisher: Wiley
Date: 22-10-2013
DOI: 10.1038/ICB.2013.55
Abstract: The generation of protective antibodies by B cells following natural infection or vaccination requires 'help' from CD4(+) T cells. T follicular helper (Tfh) cells are the specialized CD4(+) T cell subset that has evolved the appropriate mechanisms to induce the activation and differentiation of B cells into immunoglobulin (Ig) secreting cells. As such, appropriate control of Tfh cell generation and function is essential to human health as overactivation is likely to result in autoimmunity, whereas underactivation is often associated with immunodeficiency. Furthermore, an understanding of the regulation of these cells may be invaluable to improved vaccine development strategies. Traditionally Tfh cells have been identified by their anatomical location in secondary lymphoid tissues, which has hindered the study of these cells in humans as access to these tissues is often not feasible. However, recent studies have identified the circulating counterparts to tissue Tfh cells and with this has come a wealth of knowledge gained from the study of these cells in human disease. Here we review some of the recent developments on the role of human Tfh cells in health and disease.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-08-2015
Abstract: The immune system needs its full array of soldiers—including cells and the molecules they secrete—to optimally protect the host. When this isn't the case, minor infections can become chronic or even deadly. Markle et al. report the discovery of seven in iduals carrying loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. These in iduals lacked immune cells that produce the cytokine interleukin-17, causing them to suffer from chronic candidiasis. RORC-deficient in iduals also exhibited impaired immunity to mycobacterium, probably due to reduced production of the cytokine interferon-γ, a molecule not known to require RORC for its induction. Science , this issue p. 606
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.COI.2007.08.005
Abstract: Understanding the intercellular and intracellular mechanisms that maintain anergy and prevent the induction of full effector function is one avenue that may allow us to manipulate immune responses. Recent studies of T cell receptor (TCR)-proximal signaling events in different models of T cell unresponsiveness have suggested that biochemically distinct forms of anergy may exist in vivo. T cell responsiveness can be altered through the control of the intracellular pool of key second messengers, such as diacylglycerol (DAG) or the lipid modification of signaling molecules, such as the Linker for activated T cells (LAT). Studies on the molecule programmed death-1 (PD-1) and its ligands have revealed that tissue-resident signals are essential in the maintenance of T cell unresponsiveness. Thus, the emerging view is that T cell anergy is a dynamic state whose establishment and maintenance can be influenced by numerous different signaling pathways.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2022
DOI: 10.1101/2022.02.28.480959
Abstract: Mevalonate kinase deficiency (MKD) is caused by biallelic loss-of-function mutations in MVK , leading to recurrent fevers and systemic inflammation. We describe new mouse avatars of MKD bearing p.Val377Ile (the commonest variant) or deletions in Mvk . Compound heterozygous mice recapitulated the biochemical phenotype of MKD, with build-up of unprenylated GTPases and increased plasma mevalonic acid. Mice with different deficiencies in mevalonate kinase revealed new insights into the genotype-phenotype relationship and mirrored the variability in the prenylation defect in human MKD, with p.V377I homozygous mice having a milder phenotype than compound heterozygous animals. The inflammatory response to LPS was enhanced in compound heterozygous mice in vivo and elevated serum interleukin-1β was abrogated by NLRP3 inflammasome inhibition. Increased temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and defective prenylation in vitro and in vivo , highlighting increased body temperature as a likely trigger of inflammatory flares and an additional potential target for future therapeutic approaches.
Publisher: The American Association of Immunologists
Date: 03-2007
DOI: 10.4049/JIMMUNOL.178.5.2932
Abstract: An effective immune response requires the expansion and survival of a large number of activated T cells. This study compared the role of protein kinase C (PKC)θ and associated signaling molecules in the survival of activated primary CD4+ vs CD8+ murine T cells. We demonstrate that the absence of PKCθ resulted in a moderate survival defect in CD4+ T cells and a striking survival defect of CD8+ T lymphocytes. CD8+ T cells lacking the c-Rel, but not the NF-κB1 50, member of the NF-κB family of transcription factors displayed a similar impairment in cell survival as PKCθ−/− CD8+ T lymphocytes. This implicates c-Rel as a key target of PKCθ-mediated survival signals in CD8+ T cells. In addition, both c-Rel−/− and PKCθ−/− T cells also displayed impaired expression of the antiapoptotic Bcl-xL protein upon activation. Changes in Bcl-xL expression, however, did not correlate with the survival of CD4+ or CD8+ lymphocytes. The addition of protein kinase B-mediated survival signals could restore partially CD4+ T cell viability, but did not dramatically influence CD8+ survival. Active protein kinase B was also unable to restore proliferative responses in CD8+ PKCθ−/− T cells. The survival of CD4+ and CD8+ T cells deficient in either PKCθ or c-Rel, however, was promoted by the addition of IL-2. Collectively, these data demonstrate that CD4+ and CD8+ T cell survival signals are differentially programmed.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2007
Publisher: Elsevier BV
Date: 10-2016
Publisher: Wiley
Date: 09-2009
DOI: 10.1038/ICB.2009.64
Abstract: T follicular helper (T(FH)) cells are a specialized subset of CD4(+) T cells that localize to B-cell follicles, where they are positioned to provide help for the induction of optimal humoral immune responses. Key features of T(FH) cells are the expressions of CXCR5, ICOS, interleukin (IL)-21 and BCL-6. The requirements for human T(FH) cell development are unknown. Here we show that IL-6, IL-12, IL-21 and IL-23 are capable of inducing IL-21 expression in naïve CD4(+) T cells isolated from human tonsils, peripheral blood and cord blood. However, only IL-12 induced sustained expressions of CXCR5 and ICOS on these activated naïve CD4(+) T cells, and endowed them with the ability to provide increased help to B cells for their differentiation into immunoglobulin-secreting cells. The effects of IL-12 were independent of interferon-gamma and T-bet, and associated with upregulation of BCL-6 expression. Thus, these cytokines, particularly IL-12, are likely to act at an early stage during dendritic cell-mediated priming of naïve CD4(+) T cells into a T(FH) cell fate, and thus underpin antibody-mediated immunity.
Publisher: American Society of Hematology
Date: 26-04-2012
DOI: 10.1182/BLOOD-2011-11-392985
Abstract: T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4+ T cells to the Tfh lineage, because IL-12 induces naive human CD4+ T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4+ T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12–induced expression of IL-21 by human CD4+ T cells. Defective expression of IL-21 by STAT3-deficient CD4+ T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4+CXCR5+ T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
Publisher: Wiley
Date: 04-11-2011
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Publisher: Elsevier BV
Date: 08-2013
Publisher: Rockefeller University Press
Date: 17-07-2018
DOI: 10.1084/JEM.20180010
Abstract: Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected in iduals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected in iduals with p110δ inhibitors.
Publisher: Rockefeller University Press
Date: 04-01-2010
DOI: 10.1084/JEM.20091706
Abstract: Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Publisher: Wiley
Date: 04-09-2007
Publisher: Frontiers Media SA
Date: 07-03-2023
DOI: 10.3389/FIMMU.2023.1095257
Abstract: Germline CARD11 gain-of-function (GOF) mutations cause B cell Expansion with NF-κB and T cell Anergy (BENTA) disease, whilst somatic GOF CARD11 mutations recur in diffuse large B cell lymphoma (DLBCL) and in up to 30% of the peripheral T cell lymphomas (PTCL) adult T cell leukemia/lymphoma (ATL), cutaneous T cell lymphoma (CTCL) and Sezary Syndrome. Despite their frequent acquisition by PTCL, the T cell-intrinsic effects of CARD11 GOF mutations are poorly understood. Here, we studied B and T lymphocytes in mice with a germline Nethyl-N-nitrosourea (ENU)-induced Card11 M365K mutation identical to a mutation identified in DLBCL and modifying a conserved region of the CARD11 coiled-coil domain recurrently mutated in DLBCL and PTCL. Our results demonstrate that CARD11.M365K is a GOF protein that increases B and T lymphocyte activation and proliferation following antigen receptor stimulation. Germline Card11 M365K mutation was insufficient alone to cause B or T-lymphoma, but increased accumulation of germinal center (GC) B cells in unimmunized and immunized mice. Card11 M365K mutation caused cell-intrinsic over-accumulation of activated T cells, T regulatory (T REG ), T follicular (T FH ) and T follicular regulatory (T FR ) cells expressing increased levels of ICOS, CTLA-4 and PD-1 checkpoint molecules. Our results reveal CARD11 as an important, cell-autonomous positive regulator of T FH , T REG and T FR cells. They highlight T cell-intrinsic effects of a GOF mutation in the CARD11 gene, which is recurrently mutated in T cell malignancies that are often aggressive and associated with variable clinical outcomes.
Publisher: Springer Science and Business Media LLC
Date: 02-2019
DOI: 10.1007/S10875-019-00612-9
Abstract: "This porridge is too hot!" she exclaimed. So, she tasted the porridge from the second bowl. "This porridge is too cold," she said. So, she tasted the last bowl of porridge. "Ahhh, this porridge is just right," she said happily and she ate it all up. While this describes the adventures of Goldilocks in the classic fairytale "The Story of Goldilocks and the Three Bears," it is an ideal analogy for the need for balanced signaling mediated by phosphatidylinositol-3-kinase (PI3K), a key signaling hub in immune cells. Either too little or too much PI3K activity is deleterious, even pathogenic-it needs to be "just right"! This has been elegantly demonstrated by the identification of inborn errors of immunity in key components of the PI3K pathway, and the impact of these mutations on immune regulation. Detailed analyses of patients with germline activating mutations in PIK3CD, as well as the parallel generation of novel murine models of this disease, have shed substantial light on the role of PI3K in lymphocyte development and differentiation, and mechanisms of disease pathogenesis resulting not only from PIK3CD mutations but genetic lesions in other components of the PI3K pathway. Furthermore, by being able to pharmacologically target PI3K, these monogenic conditions have provided opportunities for the implementation of precision medicine as a therapy, as well as to gain further insight into the consequences of modulating the PI3K pathway in clinical settings.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2009
DOI: 10.1038/NI.1820
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
DOI: 10.1038/NCOMMS15373
Abstract: Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8 + and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and ‘superkines’. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25 + regulatory T-cells (Tregs) and results in strong expansion of CD25 − cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics.
Publisher: Wiley
Date: 07-2008
Publisher: Elsevier BV
Date: 2023
Publisher: Springer International Publishing
Date: 2022
DOI: 10.1007/978-3-031-06566-8_10
Abstract: Phosphatidylinositol-3-kinases (PI3K) control many aspects of cellular activation and differentiation and play an important role in B cells biology. Three different classes of PI3K have been described, all of which are expressed in B cells. However, it is the class IA PI3Ks, and the p110δ catalytic subunit in particular, which seem to play the most critical role in B cells. Here we discuss the important role that class IA PI3K plays in B cell development, activation and differentiation, as well as examine what is known about the other classes of PI3Ks in B cells.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 10-2015
Publisher: Wiley
Date: 22-11-2011
DOI: 10.1111/J.1749-6632.2010.05824.X
Abstract: Effective B cell-mediated immunity, including the formation of germinal centers and the generation of high-affinity memory B cells and long-lived plasma cells, is dependent on CD4(+) T cells. Immunodeficiencies that present with defects in the antibody response have provided insights into the molecular mechanisms of B cell responses and the provision of T cell help. One such immunodeficiency is X-linked lymphoproliferative disease (XLP), which results from mutations in SH2D1A, the gene encoding SLAM-associated protein (SAP). Patients with XLP present with humoral defects characterized by hypogammaglobulinemia. We now know that SAP, through its signaling downstream of multiple members of the signaling lymphocytic activation molecule (SLAM) family of cell surface receptors, plays a crucial role in many aspects of this immune response. Here, we discuss the role of SAP in the generation of humoral immunity, particularly T cell-dependent antibody responses and the generation of germinal centers.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JACI.2018.04.030
Abstract: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8 PIK3CD GOF total and EBV-specific CD8 PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8
Publisher: Rockefeller University Press
Date: 11-07-2016
DOI: 10.1084/JEM.20151467
Abstract: Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying in iduals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation.
Publisher: Wiley
Date: 03-2010
Abstract: Regulatory T (Treg) cells are crucial for maintaining peripheral tolerance and controlling T-cell responses. The generation of Treg in the thymus requires TCR triggering and CD28 costimulation. Engagement of these receptors induces a number of signalling pathways, including the activation of NF-kappaB via PKCtheta and the Bcl-10/CARMA1/MALT complex. Previous studies have shown that PKCtheta, Bcl-10 and CARMA1 are important for Treg development. It is unclear, however, whether different members of the NF-kappaB family contribute to Treg development or homeostasis. In this study, we show that Treg numbers are reduced in the absence of c-Rel but not NF-kappaB1 (p50). Furthermore, using mixed bone marrow chimeras from WT and KO animals, we demonstrate that the requirement for PKCtheta, Bcl-10 and c-Rel is T-cell intrinsic, and cannot be rescued by the presence of WT cells. Therefore, c-Rel and NF-kappaB1 have differential roles in Treg development.
Publisher: Springer Science and Business Media LLC
Date: 10-2008
DOI: 10.1038/455745A
Publisher: Frontiers Media SA
Date: 07-02-2018
Publisher: Springer Science and Business Media LLC
Date: 17-05-2013
DOI: 10.1038/NRI3447
Abstract: Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4(+) T cells, namely T follicular helper (TFH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. TFH cells are stringently regulated, as aberrant TFH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate TFH cell differentiation, function and fate should highlight targets for novel therapeutics.
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.IMMUNI.2017.06.003
Abstract: The signaling pathways regulating positive selection in germinal centers (GCs) are incompletely understood. Ersching et al. (2017) identify a critical but temporal role for the action of the kinase mechanistic target of rapamycin complex (mTORC1), which promotes key changes in GC B cells and thereby facilitates affinity maturation.
Publisher: American Society of Hematology
Date: 05-12-2013
DOI: 10.1182/BLOOD-2013-06-506865
Abstract: IL21-mediated induction of CD25 expression on naïve human B cells requires STAT3. A lack of response to IL-2 may lify humoral immunodeficiency in patients with STAT3, IL2RG, or IL21R mutations due to unresponsiveness to IL21.
Publisher: Rockefeller University Press
Date: 04-05-2015
DOI: 10.1084/JEM.20141992
Abstract: Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that in iduals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic in iduals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.
Publisher: Wiley
Date: 07-2020
DOI: 10.1111/IMCB.12348
Publisher: Rockefeller University Press
Date: 02-07-2012
DOI: 10.1084/JEM.20120994
Abstract: The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.
Publisher: Wiley
Date: 12-1999
DOI: 10.1046/J.1440-1711.1999.00874.X
Abstract: Mature T and B lymphocytes respond to receptor-delivered signals received during and following activation. These signals regulate the rates of cell death, growth, differentiation and migration that ultimately establish the behaviour patterns collectively referred to as immune regulation. We have been pursuing the philosophy that in vitro systems of lymphocyte stimulation, when analysed quantitatively, help reveal the logical attributes of lymphocyte behaviour. The development of carboxyfluorescein diacetate succinimidyl ester (CFSE) to track ision has enabled the variable of ision number to be incorporated into these quantitative analyses. Our studies with CFSE have established a fundamental link between differentiation and ision number. Isotype switching, expression of T cell cytokines, surface receptor alterations and changes to intracellular signalling components all display independent patterns of change with ision number. The stochastic aspects of these changes and the ability of external signals to independently regulate them argue for a probabilistic modelling framework for describing and understanding immune regulation.
Publisher: Wiley
Date: 07-06-2020
DOI: 10.1111/IMCB.12345
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-12-2018
DOI: 10.1126/SCIIMMUNOL.AAU6759
Abstract: Human IFN-γ–dependent immunity to mycobacteria is less compromised in IL-12Rβ2 or IL-23R deficiency than IL-12Rβ1 deficiency.
Publisher: Rockefeller University Press
Date: 16-12-2019
DOI: 10.1084/JEM.20191336
Abstract: Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.
Publisher: Rockefeller University Press
Date: 21-03-2023
DOI: 10.1084/JEM.20221020
Abstract: Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.COI.2014.01.015
Abstract: Signalling in lymphocytes through cytokine receptors is critical for their development, activation and differentiation into effector cells that mediate protection against pathogens and provide the host with protective immunological memory. The essential role of cytokine signalling has been established not only by the generation and examination of gene-targeted mice, but also 'Experiments of Nature' whereby monogenic mutations cause primary immunodeficient conditions characterised by impaired immunity to infectious diseases due to compromised lymphocyte function. Mutations in STAT3 cause autosomal dominant hyper-IgE syndrome. Here, we will review how the study of STAT3-deficient in iduals has revealed non-redundant functions of STAT3 and specific cytokines in human lymphocyte biology, and have delineated mechanisms underlying the distinct clinical features of autosomal dominant hyper-IgE syndrome.
Publisher: Frontiers Media SA
Date: 13-02-2020
Publisher: Informa UK Limited
Date: 09-2006
DOI: 10.1128/MCB.00755-06
Publisher: Springer Science and Business Media LLC
Date: 07-2010
DOI: 10.1038/NI0710-644A
No related grants have been discovered for Elissa Deenick.