Effect of IL-7 on CD4+ T cell and Th9 cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86542 | GEO | 2017/02/06
SECONDARY ACCESSION(S): PRJNA342170
REPOSITORIES: GEO
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Project description:Th9 cells are differentiated from naïve CD4+ T cells by T cell receptor (TCR) stimulation in the presence of the cytokines transforming growth factor-beta (TGF-b) and IL-4, but the molecular mechanisms by which signaling via these two cytokines control Il9 gene expression remain incompletely understood. We show here opposing functions of albumin site D-binding protein (DBP) and E2F8, an atypical member of the E2F family member of transcription factors , in controlling Th9 cell differentiation. Specifically, TGF-b and IL-4 signaling induced phosphorylation of the Serine 213 site in the linker region of the Smad3 protein (pSmad3L-Ser213) via the activation of phosphorylated MAPK p38 (p-p38). pSmad3L-Ser213, but not the phosphorylation of the C-terminal of SMAD3 (pSmad3C), was necessary and sufficient for Il9 gene transcription. We identified DBP and E2F8 as a potential activator and repressor, respectively, for Il9 gene transcription by analyzing the global chromatin accessibility and transcriptomes and discovered that pSmad3L-Ser213 was required for the increase in DBP expression but decreased E2F8 expressions during Th9 cell differentiation. We found that while DBP and E2F8 directly bound to the promoters of Il9 gene, DBP enhanced, but E2F8 suppressed, Il9 gene transcription in CD4+ T cells in response to TGF-b and IL-4 signaling, as revealed by functional gene loss- and gain-of-function studies. Notably, the Dbp-deficient and E2f8-deficient Th9 cells promoted and suppressed tumor growth, respectively, in experimental tumor models of melanoma and fibrosarcoma in mice. Importantly, DBP and E2F8 also exhibited opposing roles in regulating human TH9 differentiation in vitro. Thus, we have revealed a previously unrecognized molecular mechanism of Smad3 linker region-mediated opposing functions of DBP and E2F8 in Th9 differentiation.
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Project description:Interleukin 9 (IL-9) is a γc-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2–JAK3–STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and over- expression of BCL6 impaired Th9 differentiation. In contrast to IL-2, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6−/− cells, whereas Th9 differentiation was increased in Il21−/− or Il21r−/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6–STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process. Genome-wide transcription factors mapping and binding of STAT5B and STAT6 in mouse polarized Th9 cells treated with or without blocking antibodies to IL-2 (anti-IL-2). RNA-Seq is conducted in WT and Il2-/- mice.
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Project description:Interleukin 9 (IL-9) is a γc-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2–JAK3–STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and over- expression of BCL6 impaired Th9 differentiation. In contrast to IL-2, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6−/− cells, whereas Th9 differentiation was increased in Il21−/− or Il21r−/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6–STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process.
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