IL-12 drives the diferentiation of human T follicular regulatory cells [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252765 | GEO | 2024/04/16
REPOSITORIES: GEO
Similar Datasets
Project description:T follicular regulatory (Tfr) cells can counteract the B cell-helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cues initiating the differentiation of T regulatory (Treg) cells into Tfr cells, which is instrumental for the therapeutic manipulation of diseases associated with a Tfr cell imbalance, is still missing. Despite their opposed roles, Tfr and Tfh cell differentiation appears to be controlled by partially overlapping signals, including TCR stimulation and costimulatory molecules. However, it is still unknown if cytokines that have been shown to control the biology of human Tfh cells, including IL-12 and activin A, can influence the differentiation of Tfr cells. To address this question, we evaluated the impact of these two cytokines on the in vitro differentiation of Tfr cells. Herein, we report a role for IL-12 and down stream Stat4 chromatin binding in driving, on activated Treg cells, the induction of molecules that belong to the Tfr cell program, including CXCR5, PD-1, BCL6 and ICOS meanwhile preserving Tfr regulatory function.
2024-04-16 | GSE252764 | GEO
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: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
Project description:Differential gene expression profiling of conventional (Tconv), regulatory (Treg), follicular (TFH) helper and follicular regulatory (TFR) T-cells from control vs OX40L-Jagged-1 treated NZBWF1/j mice
2022-03-17 | GSE181433 | GEO
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.
2016-03-10 | GSE79039 | GEO
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.
2015-09-02 | GSE69756 | GEO
Project description:Leber2016 - Expanded model of Tfh-Tfr
differentiation - Helicobacter pylori infection
The parameters used in the model were
obtained from experiments conducted by the authors, previous
publications [
1,
2,
3] and
parameter optimisation carried out in the paper using particle
swarm and genetic algorithms.
This model is described in the article:
Bistability analyses of CD4+
T follicular helper and regulatory cells during Helicobacter
pylori infection.
Leber A, Abedi V, Hontecillas R,
Viladomiu M, Hoops S, Ciupe S, Caughman J, Andrew T,
Bassaganya-Riera J.
J. Theor. Biol. 2016 Jun; 398:
74-84
Abstract:
T follicular helper (Tfh) cells are a highly plastic subset
of CD4+ T cells specialized in providing B cell help and
promoting inflammatory and effector responses during infectious
and immune-mediate diseases. Helicobacter pylori is the
dominant member of the gastric microbiota and exerts both
beneficial and harmful effects on the host. Chronic
inflammation in the context of H. pylori has been linked to an
upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes,
controlled in part by the cytokine, interleukin-21. This study
investigates the differentiation and regulation of Tfh cells,
major producers of IL-21, in the immune response to H. pylori
challenge. To better understand the conditions influencing the
promotion and inhibition of a chronically elevated Tfh
population, we used top-down and bottom-up approaches to
develop computational models of Tfh and T follicular regulatory
(Tfr) cell differentiation. Stability analysis was used to
characterize the presence of two bi-stable steady states in the
calibrated Tfh/Tfr models. Stochastic simulation was used to
illustrate the ability of the parameter set to dictate two
distinct behavioral patterns. Furthermore, sensitivity analysis
helped identify the importance of various parameters on the
establishment of Tfh and Tfr cell populations. The core network
model was expanded into a more comprehensive and predictive
model by including cytokine production and signaling pathways.
From the expanded network, the interaction between TGFB-Induced
Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was
displayed to exert control over the determination of the Tfh
response. Model simulations predict that Tgif1 and RXR
respectively induce and curtail Tfh responses. This
computational hypothesis was validated experimentally by
assaying Tgif1, RXR and Tfh in stomachs of mice infected with
H. pylori.
The impulse of RXR as shown in the paper
(figure 7C) can be implemented by creating an event in the curated
SBML file.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000625.
To cite BioModels Database, please use:
BioModels Database:
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To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
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Public Domain Dedication for more information.
2015-05-25 | BIOMD0000000625 | BioModels
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: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: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