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Gene array for identifying molecules involved in IL-10 regulation during Th17 polarization

ABSTRACT: IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE15029 | GEO | 2009/03/03

SECONDARY ACCESSION(S): PRJNA114751

REPOSITORIES: GEO

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Gene array for identifying molecules involved in IL-10 regulation during Th17 polarization

Project description:IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction. Our recent studies showed that IL-6 combined with TGFbeta differed from IL-6 combined with IL-23 for IL-10 production and pathogenic activities in CD4 T cells deficient in Stat6 and T-bet, despite similar IL-17 production. We performed gene array analysis on Stat6 and T-bet double deficient cells. We rationalized that by comparing gene expression in cells treated with IL-6 plus TGFbeta versus TGFbeta alone, we would be able to identify genes specific for standard Th17 polarization, and responsible for both IL-17 and IL-10 expression. By next comparing gene expression in cells treated with IL-6 plus TGFbeta versus IL-6 plus IL-23, we could eliminate molecules involved solely in IL-17 regulation, and obtain genes specifically responsible for IL-10 regulation.

2009-03-03 | E-GEOD-15029 | biostudies-arrayexpress

Glycosylation-dependent modulation of the IL-2 signaling axis determines Th17 differentiation and IL-10 production

Project description:Metabolism plays an essential role in shaping Th cell responses including the production of pro-inflammatory cytokines. However, its effect on the production of the anti-inflammatory cytokine IL-10 has not been investigated. We show here that the glucose analogue 2-deoxyglucose (2DG) specifically inhibited Th1 and Th2 cell differentiation and accompanying IL-10 production. In contrast, 2DG promoted IL-17A production by Th17 cells, even in the presence of IL-2 known to limit Th17 differentiation, whilst simultaneously also abrogating the production of IL-10. Rather than inhibiting glycolysis, 2DG was found to act through the inhibition of glycosylation, itself critical for IL-2Ra surface expression and downstream signaling, explaining the reciprocal effect of 2DG on the Th1 and Th2 versus Th17 differentiation. The essential role of IL-2 for IL-10 production by Th17 cells was confirmed by adding IL-2 or anti-IL-2, neither of which made the cells more pathogenic. The molecular mechanism of the IL-2 driven Th17 IL-10 production may be attributed to the transcription factor c-Maf, whose expression was significantly upregulated in the presence of IL-2 signaling. The overall RNA signature of sorted IL-10+ T cells driven by IL-2, be it IL-17A+ or IL-17A-, was dominated by protein synthesis whereas that of their IL-10- counterparts by cell cycle associated processes suggesting that IL-10 secreting Th17 cells trade off self-renewal for secretory capacity. Our study thus reveals a previously unappreciated, anti-inflammatory role for IL-2 in Th17 cell production of IL-10 and identifies a novel mechanism to limit Th17 pathogenicity.

2020-03-29 | GSE129028 | GEO

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

2012-03-17 | E-GEOD-36554 | biostudies-arrayexpress

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

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]

2012-03-17 | GSE36554 | GEO

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

2012-03-17 | GSE36520 | GEO

The transcription factor c-Maf is a positive regulator of IL-10 with context-specific roles in CD4+ T cell effector function and in vivo consequences [ATAC-seq]

Project description:CD4+ T cells differentiate into distinct subsets which produce unique patterns of cytokines to eradicate pathogens, alongside IL-10 which controls immune pathology. How Il10 expression is regulated alongside the subset-specific cytokines is unclear. Using transcriptional and epigenomic profiling of CD4+ T cells from TH1 (malaria), TH2 (allergy) and TH17 (autoimmunity) disease models, we show here that c-Maf, identified as the top candidate regulator of IL-10, directly induces IL-10 across all CD4+ T cell subsets, controlling pathology in TH1 and TH2-type responses. We also report direct negative effects of c-Maf on Il2 explaining the increased Foxp3+Tregs, and direct positive effects on Rorc, as mechanisms for the decreased pathology seen in the TH17 disease model in the absence of c-Maf. Thus, c-Maf has broad yet context specific roles in directly and indirectly regulating gene expression, allowing each type of T effector immune response to occur effectively yet in a controlled fashion.

2018-02-08 | GSE106461 | GEO

The transcription factor c-Maf is a positive regulator of IL-10 with context-specific roles in CD4+ T cell effector function and in vivo consequences [RNA-seq in vitro]

2018-02-08 | GSE106463 | GEO

The transcription factor c-Maf is a positive regulator of IL-10 with context-specific roles in CD4+ T cell effector function and in vivo consequences [RNA-seq in vivo]

2018-02-08 | GSE106462 | GEO

Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation

Project description:T helper (Th) cells control host defense to pathogens. IL 12R expression is required for Th1, IL-4RM-NM-1 for Th2, and IL-6RM-NM-1/gp130 for Th17 differentiation to allow responsiveness to IL-12, IL-4, and IL-6, respectively. IL-2 via STAT5 controls Th2 differentiation by regulating the Th2 cytokine gene cluster and Il4ra expression. Here we show that IL-2 regulates Th1 differentiation, inducing STAT5-dependent IL-12RM-NM-22 and T-bet expression, with impaired human Th1 differentiation when IL-2 was blocked. Th1 differentiation was also impaired in mouse Il2-/- T cells but restored by IL-12RM-NM-22 expression. Consistent with IL-2M-bM-^@M-^Ys inhibition of Th17 differentiation, IL-2 decreased Il6ra and Il6st/gp130 expression, and Il6st augmented Th17 differentiation even when IL-2 was present. Thus, IL-2 influences T-cell differentiation by modulating cytokine receptor expression to help specify/maintain differentiated states. Genome-wide mapping of STAT1,STAT4,STAT5A,STAT5B binding to their target genes in Th1 or human CD4+ cells was conducted

2011-04-24 | E-GEOD-27158 | biostudies-arrayexpress

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