Gene expression profile of FoxP3+ CD4+ follicular regulatory T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE101611 | GEO | 2019/11/21
REPOSITORIES: GEO
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Project description:CD4+CXCR5+Foxp3+ T follicular regulatory (TFR) cells control the germinal center responses. Like follicular helper T-cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. NFATc1/αA is necessary to overcome TFR-expressed B lymphocyte-induced maturation protein (Blimp-1), which can directly repress Cxcr5. Blimp-1 then reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA, which strengthens the follicular development of Tregs, but bears the inherent risk of causing an ex-Treg phenotype.
2022-01-01 | GSE172075 | GEO
Project description:Foxp3+Tregcells are essential modulators of immune responses but under specific conditions can acquire inflammatory properties and potentially contribute to disease pathogenesis. Here we show that the transcription factor Blimp1 is a critical regulator of Foxp3+Treg functional plasticity. The intrinsic expression of Blimp1 was required to prevent Treg from producing Th17-associated cytokines and acquiring an inflammatory phenotype while preserving Foxp3 expression. Mechanistically, Blimp1 acts as a direct repressor of the Il17a/Il17f genes in Foxp3+Treg and binding of Blimp1 at this locus is associated with altered chromatin status, reduced binding the co-activator p300, unaltered binding of the Th17-asssociated transcription factor RORt and more abundant binding of IRF4, which was required for the production of IL17A in Blimp1-deficient Foxp3+Tregcells, as shown by IRF4 siRNA-mediated knockdown. Consistent with their capacity to produce inflammatory cytokines, Blimp1-deficient Foxp3+Treg exacerbate Th17-mediated inflammation in vivo indicating that Blimp1 is required to prevent Treg cells from acquiring pathogenic properties
2019-01-08 | GSE84827 | GEO
Project description:ICOS is a T cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 upregulation. Further, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.
2023-02-02 | GSE164995 | GEO
Project description:Objective: T follicular regulatory (Tfr) cells express CXC chemokine receptor type 5. They migrate into germinal centers and suppress T follicular helper (Tfh) and B cells for regulating antibody production. Tumor necrosis factor (TNF) inhibitors are used in inflammatory diseases; however, autoantibody and anti-drug antibody production is challenging. As TNF receptor 2 (TNFR2) signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on Tfr cells. Methods: Tfr, Tfh, and naive B cells were obtained from human peripheral blood. Tfr cells were stimulated with MR2-1 (anti-TNFR2 agonistic antibody) and their proliferation, Forkhead box P3 (Foxp3) expression, and surface molecules were evaluated by flow cytometry. Tfh/B-cell proliferation and B-cell IgM production and differentiation in co-cultures with MR2-1-stimulated Tfr cells were examined. Results: TNFR2 expression was higher on Tfr cells than conventional T cells. MR2-1 altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression were induced by MR2-1. Inducible costimulator and program death-1 were dramatically upregulated in MR2-1-stimulated Tfr cells and significantly suppressed Tfh/B-cell proliferation, IgM production, and B-cell differentiation. Tfr cells treated with MR2-1 migrated according to the CXCL13 gradient. Conclusion: TNFR2 signaling in Tfr cells regulates Tfh and B-cell population. Aberrant antibody production during TNF inhibitor treatment might be associated with TNFR2 signaling inhibition in Tfr cells, suggesting TNFR1-specific inhibition as a better therapeutic strategy than pan-TNF inhibition. TNFR2-treated Tfr cells may serve as prospective candidates for cell-based therapy of autoimmune diseases.
2021-12-20 | GSE161835 | GEO
Project description:Tfr cells from Ezh2 floxed FoxP3 Cre mice
2019-01-25 | GSE124881 | GEO
Project description:In response to infection, antigen-specific CD8+ T cells are primed in the T cell zone of secondary lymphoid organs and differentiate into cytotoxic effector T (TC) cells. Concurrently, CD4+ T cells differentiate into follicular helper T (TFH) cells that localize to B cell follicles and promote protective antibody responses. During unresolved infections, however, some viruses including human immunodeficiency virus (HIV) or Epsteinâ??Barr virus (EBV) escape immune control and persist in TFH cells and B cells, respectively. Exclusion of Tc cells from B cell follicles is thought to be a major mechanism of immune evasion. New strategies are therefore needed to eradicate infected cells in follicles for a permanent cure. Using mouse infection models and human samples, we here identify a specialized group of TC cells expressing the chemokine receptor CXCR5 that can selectively enter B cell follicles and eradicate infected TFH and B cells. We demonstrate that differentiation of these cells, which we term follicular cytotoxic T (TFC) cells, requires the transcription factors Bcl6, E2A and Tcf1, whereas the transcriptional regulators Blimp1, Id3 and Id2 inhibit their development. We demonstrate that Blimp1 and E2A directly regulate Cxcr5 expression, and together with Bcl6 and Tcf1 form a transcriptional circuit that guides the TFC differentiation. The identification of a follicular subset of TC cells has far reaching implications for developing better strategies for the control of infections that target B cells and TFH cells and for the eradication of B cell derived malignancies. There is no associated input. The E2A Bio-ChIP-seq was performed with total thymocytes from Tcf3Bio/Bio Rosa26BirA/BirA mice
2016-08-01 | E-GEOD-84974 | biostudies-arrayexpress
Project description:T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity. RNAseq analyses of WT and Stim1Stim2 DKO follicular T cells and non-follicular T cells; 4-6 mice per cohort in duplicates. Mice were infected for 10 days with LCMV.
2016-03-10 | E-GEOD-79039 | biostudies-arrayexpress
Project description:FOXP3+ T follicular regulatory cells (Tfrs) control germinal center (GC) responses by steering antibody formation away from self-reactivity and toward microbe/vaccine recognition. As originally described, murine Tfr cells descend exclusively from thymically-derived, self-antigen recognizing, T regulatory cells (Tregs), but newer animal models suggest vaccine-recognizing T follicular helper (Tfh) cells can assume regulatory roles as GCs mature. To test the hypothesis that the human Tfr pool is heterogenous in function and provenance, we used paired TCRVA and TCRVB sequencing to distinguish tonsillar Tfr cells clonally related to the natural Tregs (nTfr) from those induced from Tfh cells (iTfr). Through in silico predictions and in vitro tonsillar organoid lineage tracking, we identified a Tfh to iTfr developmental trajectory that passed through a distinct CD25hiBLIMP1+FOXP3- transitional stage. The genes and proteins that iTfr and nTfr cells express differentially were utilized as handles to precisely pinpoint the in situ locations of cells from each subset via multi-plex microscopy and to establish divergent functional adaptations. In total, we characterize human iTfr cells as a GC-resident CD38+ Tfr subset that descend from Tfh lineage cells to gain suppressive qualities while retaining their capacity for GC B-cell help.
2023-02-23 | GSE214572 | GEO
Project description:Background information: Antibody responses to most infectious and food protein antigens depend on help to B cells from specialised T follicular helper (Tfh) cells. A subset of Foxp3+ regulatory T cells (Tregs) has been described in mice, with a prominent role in repressing germinal center reactions that are critical for memory B cell formation and long-lived antibody responses. These specialised Tregs co-opt the Bcl-6-dependent Tfh differentiation pathway in order to access the B cell-rich follicles and have therefore been designated as T follicular regulatory (Tfr) cells. Preliminary results: We identified a unique Bcl-6-expressing follicular regulatory T cell in human secondary lymphoid tissue, designated hereafter as Tfr2 cells, that lacks Foxp3 expression and the thymic-imprinted Foxp3 methylation pattern, but shares expression of key Treg molecules. Interestingly, 25% of these cells are the predominant source of T cell-derived IL-10 in human tonsil, an important cytokine with immunomodulatory properties. Aims of this study: We performed transcriptional profiling using affymetrix microarrays to interrogate wether IL-10 producing vs non producing human Tfr2 cells were fundamentally different subsets. 2 cell types (IL-10+ vs IL10- TFR2 cell subsets) obtained from 3 different tonsil donors (biological replicates)
2016-04-05 | E-GEOD-79887 | biostudies-arrayexpress
Project description:In response to infection, antigen-specific CD8+ T cells are primed in the T cell zone of secondary lymphoid organs and differentiate into cytotoxic effector T (TC) cells. Concurrently, CD4+ T cells differentiate into follicular helper T (TFH) cells that localize to B cell follicles and promote protective antibody responses. During unresolved infections, however, some viruses including human immunodeficiency virus (HIV) or Epstein–Barr virus (EBV) escape immune control and persist in TFH cells and B cells, respectively. Exclusion of Tc cells from B cell follicles is thought to be a major mechanism of immune evasion. New strategies are therefore needed to eradicate infected cells in follicles for a permanent cure. Using mouse infection models and human samples, we here identify a specialized group of TC cells expressing the chemokine receptor CXCR5 that can selectively enter B cell follicles and eradicate infected TFH and B cells. We demonstrate that differentiation of these cells, which we term follicular cytotoxic T (TFC) cells, requires the transcription factors Bcl6, E2A and Tcf1, whereas the transcriptional regulators Blimp1, Id3 and Id2 inhibit their development. We demonstrate that Blimp1 and E2A directly regulate Cxcr5 expression, and together with Bcl6 and Tcf1 form a transcriptional circuit that guides the TFC differentiation. The identification of a follicular subset of TC cells has far reaching implications for developing better strategies for the control of infections that target B cells and TFH cells and for the eradication of B cell derived malignancies. There is no associated input.
2016-08-01 | GSE84974 | GEO