Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA176554 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR579523_1.fastq.gz | Fastqsanger.gz | |||
| SRR579523_2.fastq.gz | Fastqsanger.gz | |||
| SRR579524_1.fastq.gz | Fastqsanger.gz | |||
| SRR579524_2.fastq.gz | Fastqsanger.gz | |||
| SRR579525_1.fastq.gz | Fastqsanger.gz |
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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.
2014-02-20 | E-GEOD-41317 | 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
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.
2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress
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.
2015-07-01 | GSE63204 | GEO
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 follicular helper (Tfh) cell is a unique T cell subset specialized in promoting germinal center reactions. Bcl6 has been identified as an obligatory transcription factor in Tfh cells; however, the molecular mechanism underlying Bcl6 function still remains unknown. Here, we combined genome-wide Bcl6 occupancy and transcriptome profiling to systemically analyze Bcl6 targets in Tfh cells. We found that Bcl6 exhibits unique binding preferences in Tfh cells from those in Th9, B cells and macrophage and its binding is closely associated with decrease in 5-hydroxymethylcytosine (5hmC). Importantly, Bcl6 directly binds to the IL-7R/CD127 gene and suppresses its expression. Bcl6 also binds the same sequences recognized by signal transducer and activator of transcription (STAT) 5, downstream of IL-7R. Bcl6 promotes CD127loPDhi Tfh cell differentiation; deletion of the Bcl6 gene in T cells results in enhanced IL-7R-STAT5 signaling and substantial expansion of CD127hiPDlo non-Tfh cells. Our study thus systemically examines Bcl6-controlled regulatory networks and provides novel insights into its biological functions in Tfh cells.
2016-01-31 | GSE72188 | GEO
Project description:Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation, and guide their differentiation and Ig isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-g. IL-21 and IFN-g are co-expressed by Tfh cells during acute and chronic infections, but transcriptional regulation of these cytokines in the GC is incompletely understood. We show that the Th1 transcriptional regulators T-bet and STAT4 are co-expressed with Bcl6 in Tfh cells following acute murine lymphocytic choriomeningitis virus infection, albeit with temporal decline in T-bet expression as the GC response evolved. T-bet was important for Tfh cell production of IFN-g, but not IL-21, and for the generation of a robust germinal center reaction. STAT4, phosphorylated in Tfh cells upon infection, was required for their expression of T-bet and Bcl6, and that of IFN-g and IL-21. These data indicate that T-bet is concomitantly expressed with Bcl6 in Tfh cells and is required alongside STAT4 phosphorylation to coordinate Tfh cell IL-21 and IFN-g production, and for promotion of the GC response following acute viral challenge.
2017-11-22 | GSE105807 | GEO
Project description:Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation, and guide their differentiation and Ig isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-g. IL-21 and IFN-g are co-expressed by Tfh cells during acute and chronic infections, but transcriptional regulation of these cytokines in the GC is incompletely understood. We show that the Th1 transcriptional regulators T-bet and STAT4 are co-expressed with Bcl6 in Tfh cells following acute murine lymphocytic choriomeningitis virus infection, albeit with temporal decline in T-bet expression as the GC response evolved. T-bet was important for Tfh cell production of IFN-g, but not IL-21, and for the generation of a robust germinal center reaction. STAT4, phosphorylated in Tfh cells upon infection, was required for their expression of T-bet and Bcl6, and that of IFN-g and IL-21. These data indicate that T-bet is concomitantly expressed with Bcl6 in Tfh cells and is required alongside STAT4 phosphorylation to coordinate Tfh cell IL-21 and IFN-g production, and for promotion of the GC response following acute viral challenge.
2017-11-22 | GSE105806 | GEO
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:Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be found. Here we identified that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in Th cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that AREG-EGFR signaling induces HIF1α, which binds and transactivates IL-9, IRF4 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppress their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.
2021-06-15 | GSE163056 | GEO