Transcriptional modifications driven by STING activation in polarizing TH1 and Th9 cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147300 | GEO | 2022/02/18
REPOSITORIES: GEO
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Project description:We found that IL-7 pretreatment enhanced Th9 differentiation. To clarify the underlying mechanisms, we examine the gene expression profiles of CD4+ T cell and Th9 cells with or without IL-7 pretreatment. In Th9 cells, we found that Th9 related genes were greatly increased in IL-7 Th9 group, which demonstrated an enhanced Th9 differentiation. In CD4+ T cells, we found that IL-7 treatment resulted in a global gene expression change especially on chromatin remodeling related genes, which facilitated the entry of transcriptional factor to the Il9 promoter region and promoted Il9 transcription.
2017-02-06 | GSE86542 | GEO
Project description:Transcriptional modifications driven by STING activation in polarizing TH1 and Th9 cells
| PRJNA613701 | ENA
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.
2022-08-09 | GSE182472 | GEO
Project description:T helper 9 (TH9) cells are important for the development of inflammatory and allergic diseases. The TH9 transcriptional network converge signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as strong inducer of mouse and human TH9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under TH9 and TH9-TL1A polarizing conditions. In vivo, using a T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3-/- TH9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role of BATF3 in TH9-induced mucosal inflammation.
2019-01-08 | GSE106926 | GEO
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.
2014-02-20 | E-GEOD-41317 | biostudies-arrayexpress
Project description:Th cell differentiation is transcriptionally regulated, relying on the induction of “lineage-defining” transcription factors. We report that formation of super-enhancers is critical in robust induction of Th9 cells and that assembly of the Il9 super-enhancers requires OX40-triggered chromatin H3K27 acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation. This allows binding of the super-enhancer factor Brd4 to initiate assembly of the super-enhancer complex, which in turn drives robust Th9 induction. Thus, Th9 cells are induced in massive numbers upon OX40 costimulation and disruption of super-enhancers abolished Th9 induction in vitro and inhibited Th9-mediated allergic airway inflammation in vivo. Our data identify super-enhancers as a key mechanism of Th9 induction and uncover a new mechanism of Th cell differentiation.
2018-01-11 | GSE102940 | GEO
Project description:Systemic sclerosis (SSc) is a chronic autoimmune disease characterized with fibrosis of skin and multiple vital organs, but the immunological pathogenesis of SSc remains largely unknown. We show here that microRNA-19b (miR-19b) promotes IL-9-producing CD4+ T cells (Th9) that exacerbate SSc. Specifically, TGF-b plus IL-4 induced expression of TNF receptor associated factor 6 (TRAF6) through phosphorylated Smad3 linker region site Serine 213 (p-Smad3L-Ser213) and activated it through K63 ubiquitination by suppressing the leucine-rich-repeat-containing protein 3 (NLRC3). TRAF6 consequently formed complex with and activated TGF-b activated kinase 1 (TAK1). TAK1 promoted nuclear factor kappa B (NFκB) p65 activation, which then specifically upregulated miR-19b. miR-19b activated Il9 gene expression and promoted Th9 differentiation by directly targeting and suppressing atypical E2F family member E2f8 gene, a repressor for Il9 gene transcription. Importantly, Th9 cells played a critical role in the development and pathogenesis of experimental SSc by promoting the fibrosis in mice induced with Bleomycin. miR-19b and IL-9 were increased in CD4+ T cells in experimental SSc in mice and also in patients with SSc. Strikingly, inhibition of miR-19b resulted in fewer Th9 cells and attenuated fibrotic manifestations and ameliorated the disease in SSc mice. Our study identifies miR-19b as a key factor of Th9 cells that are involved in the pathogenesis of SSc. Our findings should have clinical implications for patients with SSc.
2024-08-21 | GSE269954 | GEO
Project description:The TNF family member TL1A (TNFSF15) co-stimulates several T helper subsets and promotes T cell-dependent models of inflammatory diseases, including inflammatory bowel diseases (IBD) and allergic lung disease. TL1A polymorphisms confer susceptibility to IBD and have been associated with disease severity. In this study, we identified TL1A as a strong inducer of TH9 cell differentiation in vitro. Mechanistically, TL1A induced NF-B signaling and down-stream STAT6 activation and facilitated cooperative binding of BATF, BATF3, and IRF4 to the Il9 promoter. In vivo, utilizing an adoptive T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation and blocking anti-IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role for IL-9 in TL1A-induced mucosal inflammation.
2019-01-08 | GSE60362 | GEO
Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.
2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress
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.
2014-02-20 | GSE41317 | GEO