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Human T follicular helper cells seed the germinal center-resident regulatory pool

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214572 | GEO | 2023/02/23

REPOSITORIES: GEO

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Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

Project description:T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells. TFR, TFH, TREG and bulk CD4 cells were sorted from spleens of 5 uninfected and 5 infected RM.

2015-09-02 | E-GEOD-69756 | biostudies-arrayexpress

Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

2015-09-02 | GSE69756 | GEO

Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity

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

Transcriptional profiling of IL-10 producing vs non producing human TFR2 cells

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)

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Follicular Regulatory T Cells Regulate the Development of Cytotoxic-like Follicular Helper T Cells

Project description:T follicular regulatory (TFR) cells are found in the germinal center (GC) response and help shape the antibody (Ab) response. Whether TFR cells have a suppressive role, a helper role or both types of roles in the GC is unclear. Here, we addressed TFR cell function using 3 different strains of TFR cell mutant mice. After immunization, GC B cells but not T follicular helper (TFH) cell positively correlated with TFR cell levels. Using a gene profiling approach, we found that TFH cells from TFR-deficient mice showed strong up-regulation of granzyme B (Gzmb) and other effector CD8 T cell genes, many of which were Stat4 dependent. This aberrant cytotoxic T cell gene profile was increased in TFR-deficient mice crossed on a pro-inflammatory background. We detected Gzmb+ and Eomesodermin+ TFH cells and a higher rate of apoptotic GC B cells in the absence of TFR cells. Klrg1+ TFH cells expressed higher Gzmb and less IL-4 and IL-21. Our data show that TFR cells repress the development of abnormal cytotoxic TFH cells that correlate with a lower GC and Ab response. This data shows a novel mode of helper function for TFR cells in the GC response.

2019-06-29 | GSE133533 | GEO

ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

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

Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity

2016-03-10 | GSE79039 | GEO

NFATc1/αA and Blimp-1 support the follicular and effector phenotype of Tregs

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

Transcriptional profiling of IL-10 producing vs non producing human TFR2 cells

2016-04-05 | GSE79887 | GEO

TNF-receptor 2 signaling enhances suppressive abilities in human circulating T follicular regulatory cells

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

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