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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE164995 | GEO | 2023/02/02

REPOSITORIES: GEO

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ICOS-deficient Treg cells can prevent spontaneous autoimmunity but are impaired in controlling acute inflammation

Project description:ICOS is induced in activated T cells and its main role is to boost differentiation and function of effector T cells. ICOS is also constitutively expressed in a subpopulation of Foxp3+ regulatory T cells under steady-state condition. Studies using ICOS germline knockout mice or ICOS-blocking reagents suggested that ICOS has supportive roles in regulatory T (Treg) cell homeostasis, migration, and function. To avoid any compounding effects that may arise from ICOS-deficient non-Treg cells, we generated a conditional knockout system in which ICOS expression is selectively abrogated in Foxp3-expressing cells (ICOS FC mice). Compared to Foxp3-Cre control mice, ICOS FC mice showed a minor numerical deficit of steady-state Treg cells but did not show any signs of spontaneous autoimmunity, indicating that tissue-protective Treg populations do not heavily rely on ICOS costimulation. However, ICOS FC mice showed more severe inflammation in oxazolone-induced contact hypersensitivity, a model of atopic dermatitis. This correlated with elevated numbers of inflammatory T cells expressing IFN-γ and/or TNF-α in ICOS FC mice compared with the control group. In contrast, elimination of ICOS in all T cell compartments negated the differences, confirming that ICOS has a dual positive role in effector and Treg cells. Single-cell transcriptome analysis suggested that ICOS-deficient Treg cells fail to mature into T-bet+CXCR3+ “Th1-Treg” cells in the draining lymph node. Our results suggest that regimens that preferentially stimulate ICOS pathways in Treg cells might be beneficial for the treatment of Th1-driven inflammation.

2022-07-08 | GSE185254 | GEO

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

Gene expression profile of FoxP3+ CD4+ follicular regulatory T cells

Project description:Follicular regulatory T cells (TFR) are a major cellular source of negative regulation of GC antibody responses. Blimp1 is expressed by the majority of TFR cells within B cell follicles during immune responses, as well as by other tissue-specific subsets of effector Treg (eTreg). However, the potential impact of FoxP3-specific Blimp1 deletion on TFR differentiation and suppressive activity has not been evaluated. To better understand the role of Blimp1 in regulation of TFR differentiation and function, we profiled the differential gene expression in Blimp1-deficient TFR cells compared to WT control TFR cells.

2019-11-21 | GSE101611 | GEO

scRNA-seq of human Tfh, Tfr and Treg cells sorted from Tonsil, Iliac Lymph Node and PBMCs

Project description:The datasets were obtained to investigate the transcriptional profile of Tfh, Tfr and Treg cells isolated from different human tissues. The comparison between lymphoid tissues with different frequency of the most mature Tfh and Tfr cells allows the investigation of maturation as well as tissue adaptation of those different cell subsets. To address these issues, three different cell populations from three different tissues were sorted by index sorting, with Tfh cells as CD4+CXCR5+ICOS+; Tfr cells as CD4+CXCR5+CD25+ and Treg cells as CD4+CXCR5-CD25+. Smart-seq2 protocol was used mRNA library preparations.

2021-04-22 | E-MTAB-10364 | biostudies-arrayexpress

ICOS-expressing Treg cells influence the composition of anti-tumor CTL population

Project description:The role of ICOS in anti-tumor T cell responses and overall tumor progression has been controversial. Here, we compared tumor progression in mice lacking ICOS only in Treg cells or in all T cells. We found that Treg-specific ICOS knockout reduces the overall tumor burden compared to Cre control mice with increased T effector/Treg ratios in the tumor. In contrast, there was no difference in the tumor burden in mice lacking ICOS in all the T cell compartments. This suggests a dual role of ICOS costimulation in promoting pro- and anti-tumor T cell responses. Consistent with reduced tumor burden, we found that Treg-specific deletion of ICOS leads to an increase of CD8+ CTLs that express high levels of granzyme B and perforin. Moreover, single-cell transcriptome analysis revealed an increase of Ly108hiEomeshi CD8+ T cell subset at the cost of Ly108hiT-bethi subset in Treg-specific knockout mice. These results suggest that ICOS-expressing Treg cells suppress CTL maturation process at the level of Eomes upregulation, a critical step known to drive perforin expression and cytotoxicity. Collectively, our data imply that cancer immunotherapies using ICOS agonist antibodies would work better in Treg-low tumors or when they are combined with regimens that deplete tumor-infiltrating Treg cells.

2024-07-18 | GSE226471 | GEO

IL-12 drives the diferentiation of human T follicular regulatory cells [CUT&RUN]

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

IL-12 drives the diferentiation of human T follicular regulatory cells [RNA-seq]

2024-04-16 | GSE252765 | 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

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.

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