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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]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE106463 | GEO | 2018/02/08

REPOSITORIES: GEO

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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 vivo]

2018-02-08 | GSE106462 | GEO

Project Title: Proteome analysis of CD4+ T cell subsets

Project description:Functionally distinct CD4+ helper T (Th) cell subsets, such as Th1, Th2, Th17, and regulatory T cells (Treg), play a pivotal role in the host-defense against pathogen invasion and the pathogenesis of inflammatory disorders. In this project, DIA-MS-based proteome analysis was performed on naïve CD4+ T, Th0, Th1, Th2, Th17 and iTreg cells using Q Exactive HF-X (Thermo Fisher Scientific) to search for proteins that differ among the cell subsets.

2023-01-04 | PXD036065 | JPOST Repository

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

2009-03-03 | GSE15029 | GEO

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

Lipidomic analysis of CD4+ T-cell subsets (Th1,Th2,Th17 and iTreg cells) (part I)

Project description:Part 1/5: It includes lipidomic analysis of CD4+ T-cell subsets(Th1,Th2,Th17 and iTreg cells)and their paired controls(Th0 cells).

2021-01-28 | ST001676 | MetabolomicsWorkbench

Sen2021 - HTimmR - A generic human CD4+ T-cell model

Project description:A generic genome-scale metabolic model (GEMs) of human CD4+ T-cells. Several cell-specific GEMs for CD4+ T-cell subsets such as Th1, Th2, Th17 and iTreg cells derived from "HTimmR" are included as additional files. The model formats are compatible with RAVEN v.2.0 toolbox.

2023-03-29 | MODEL2101270002 | BioModels

Profiling of human CD4+ T subsets identifies a Th2-specific non-coding RNA GATA3-AS1

Project description:Host defense against diverse pathogens involves the recruitment and differentiation of CD4+ T effector subsets including T helper 1 (Th1), Th2, Th17 and induced regulatory T (Treg) cells. Surface phenotype studies have revealed subset-specific surface markers for the identification and purification of human primary CD4+ T effector subsets. In the present study, we aimed to characterize the mRNA and large intergenic non-coding RNA (lincRNA) expression differences between human primary CD4+ T effector subsets and identify potential subset-specific genes. To achieve this goal, mRNA and lincRNA microarray profiling of flow cytometry-sorted human primary Th1, Th2, Th17 and Treg cells was performed. Principal component and pathway analyses revealed subset-specific gene expression patterns. A Th2-specific lincRNA, GATA3-AS1, also termed FLJ45983, was identified in primary immune cells and tissues, as well as in in vitro polarized CD4+ T effector subsets. Further analysis showed that GATA3-AS1 was a potential diagnostic marker in allergy, a Th2-associated disease. This first systematic genome-wide analysis of gene expression differences between primary CD4+ T effector subsets may help to identify novel regulatory protein-coding genes and lincRNAs regulating CD4+ T cell subset differentiation, as well as potential diagnostic markers. As an example, we identified a GATA3-associated Th2-specific marker lincRNA GATA3-AS1. Gene expression microarray analysis of flow-cytometry sorted human primary naÃ¯ve CD4+ T cells, CD4+ T central memory cells, Th1, Th2, Th17 and Treg cells from buffy coat of four healthy controls Gene expression microarray analysis was performed using SurePrint G3 Human Gene Expression 8X60K microarray.

2013-06-01 | E-GEOD-43005 | biostudies-arrayexpress

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

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

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