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The transcriptional repressor Gfi1 inhibits the induction of Th1 program in activated CD4 T cells [ChIP-seq]

ABSTRACT: The transcriptional repressor Gfi1 promotes Th2 cell development and inhibits Th17 and inducible regulatory T cell differentiation. However, the contribution of Gfi1 to Th1 cell differentiation and Th1-type immune responses has not been clarified yet. We herein demonstrate that Gfi1 inhibits the activation of Th1 program in CD4 T cells. The activated Gfi1-deficient naïve CD4 T cells spontaneously develop into Th1 cells in an IL-12- and IFN-g-independent manner. The increased in vivo Th1-type immune response in Gfi1-deficient mice is confirmed using murine model of nickel allergy and delayed-type hypersensitivity. The expressions of Th1-related transcription factors including Tbx21, Eomes, Atf3, Runx1, Runx2 and Runx3 are increased in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 are identified as candidates for direct target of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and represses histone H3K4 methylation levels. Together, these findings establish a novel role of Gfi1 in inhibiting Th1 cell differentiation and Th1-type immune response.

ORGANISM(S): Mus musculus

PROVIDER: GSE70893 | GEO | 2016/04/11

SECONDARY ACCESSION(S): PRJNA289878

REPOSITORIES: GEO

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Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells

Project description:The transcriptional repressor Gfi1 promotes Th2 cell development and inhibits Th17 and inducible regulatory T cell differentiation. However, the contribution of Gfi1 to Th1 cell differentiation and Th1-type immune responses has not been clarified yet. We herein demonstrate that Gfi1 inhibits the activation of Th1 program in CD4 T cells. The activated Gfi1-deficient naïve CD4 T cells spontaneously develop into Th1 cells in an IL-12- and IFN-g-independent manner. The increased in vivo Th1-type immune response in Gfi1-deficient mice is confirmed using murine model of nickel allergy and delayed-type hypersensitivity. The expressions of Th1-related transcription factors including Tbx21, Eomes, Atf3, Runx1, Runx2 and Runx3 are increased in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 are identified as candidates for direct target of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and represses histone H3K4 methylation levels. Together, these findings establish a novel role of Gfi1 in inhibiting Th1 cell differentiation and Th1-type immune response.

2016-04-11 | GSE70829 | GEO

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Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. CD103+ Th1 and Th1 cells are profiled for mRNA expression

2012-03-17 | E-GEOD-36520 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent]

Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. Th9+IFNgamma and Th9 cells are profiled for mRNA expression

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Opposing Roles of STAT1 and STAT3 in IL-21 Function in CD4+ T cells

Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.

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Eomes+ natural Th1 (nTh1) T cells share functional features with classical Th1 (cTh1) cells.

Project description:Identification of intrathymic Eomes+ natural Th1 cells creates a novel idea that there is more than one way for the generation of innate CD4 T cells. To more deeply characterize this type of innate T cells, we compared the gene expression profile between nTh1 cells generated in CIITAtg mice and classic Th1 cells differentiated from naive CD4 T cells in Th1-polarizing condition.

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Eomes is sufficient to regulate IL-10 expression and cytotoxic effector molecules in murine CD4+ T cells

Project description:The T-box transcription factors T-bet and Eomesodermin regulate type 1 immune responses in innate and adaptive lymphocytes. T-bet is widely expressed in the immune system but was initially identified as the lineage-specifying transcription factor of Th1 CD4+ T cells, where it governs expression of the signature cytokine IFN-g and represses alternative cell fates like Th2 and Th17. T-bet’s paralog Eomes is less abundantly expressed and Eomes+ CD4+ T cells can mostly be found in the context of persistent antigen exposure, like bone marrow transplantation, chronic infection or inflammation as well as malignant disorders. However, it has remained unresolved whether Eomes executes similar transcriptional activities as T-bet in CD4+ T cells. Here we show in a novel genetic model that the expression of Eomes in CD4+ T cells drives a distinct transcriptional program that shows only partial overlap with T-bet. We found that Eomes was sufficient to induce the expression of the immunoregulatory cytokine IL-10 and, together with T-bet, promoted a cytotoxic effector profile, including Prf1, Gzmb, Gzmk, Nkg7 and Ccl5, while repressing alternative cell fates. Our results demonstrate that Eomes+ CD4+ T cells, which are often found in the context of chronic antigen stimulation, are likely to be a unique CD4+ T cell subset with the potential to limit inflammation and immunopathology as well as to eliminate antigen-presenting and malignant cells.

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Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix]

2012-03-17 | GSE36520 | GEO

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent]

2012-03-17 | GSE36554 | GEO

Genome-wide analysis of gene expression in WT and Erk2 deficient CD4 T cells

Project description:Effective immune responses depend upon appropriate T cell differentiation in accord with the nature of an infectious agent, and the contingency of differentiation depends minimally on T cell antigen receptor, co-receptor, and cytokine signals. In this reverse genetic study we show that the Map Kinase, Erk2, is nonessential for T cell proliferation in the presence of optimum co-stimulation. Instead, it has opposite polar effects on T-bet and Gata3 expression and hence on Th1 and Th2 differentiation. Alternatively, in the presence of TGFbeta, the Erk pathway suppresses a large program of gene expression effectively limiting the differentiation of Foxp3+ T reg cells. In the latter case, the mechanisms involved include suppression of Gata3 and Foxp3, induction of Tbx21, phosphorylation of Smad2,3, and possibly suppression of Socs2, a positive inducer of Stat5 signaling. Consequently, loss of Erk2 severely impeded Th1 differentiation while enhancing the development of Foxp3+ induced T regulatory cells. Selected profiles of gene expression under multiple conditions of T cell activation illustrate the opposing consequences of Erk pathway signaling. Analysis of the Th1 and iTreg differentiation regulated by Erk2. Total RNA obtained from WT or Erk2 deficient CD4 T cells in different conditions.

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