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Induction and molecular signature of pathogenic Th17 cells

ABSTRACT: TGF-beta3 produced by developing Th17 cells induces highly pathogenic T cells that are functionally and molecularly distinct from TGF-beta1-induced Th17 cells. The microarray data represent a distinct molecular signature for pathogenic versus non-pathogenic Th17 cells. Total of seven groups with two to four samples per group from two independent experiments. The no cytokines group (Th0) was used as a control to normalize the data. 7 groups: B6: (IL-1beta, IL-6) B623: (IL-1beta, IL-6, IL-23) T16: (TGF-beta1, IL-6) T1623: (TGF-beta1, IL-6, IL-23) T36: (TGF-beta3, IL-6) T3623: (TGF-beta3, IL-6, IL-23) NOCYTO: no cytokines

ORGANISM(S): Mus musculus

SUBMITTER: Youjin Lee

PROVIDER: E-GEOD-39820 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Induction and molecular signature of pathogenic TH17 cells.

Lee Youjin Y Awasthi Amit A Yosef Nir N Quintana Francisco J FJ Xiao Sheng S Peters Anneli A Wu Chuan C Kleinewietfeld Markus M Kunder Sharon S Hafler David A DA Sobel Raymond A RA Regev Aviv A Kuchroo Vijay K VK

Nature immunology 20120909 10

Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T(H)17 cells are main drivers of autoimmune tissue injury. However, not all T(H)17 cells are pathogenic; in fact, T(H)17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of T ...[more]

PMID: 22961052

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Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-β Signaling: ChIPSeq

Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (Th17) cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.

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Induction and molecular signature of pathogenic Th17 cells

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Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity1-4. Crucial for T helper17 (Th17) cells in vivo5,6, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification7-10. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Mouse T helper 17 cell differentiation with or without TGFB

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2020-03-25 | PXD016633 | Pride

Induction of pathogenic Th17 cells by salt inducible kinase SGK-1 (SGK-1 KO)

Project description:Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions2. Previous studies have shown that IL-23 signaling reinforces the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R)3. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), as an essential node downstream of IL-23 signaling, critical for regulating IL-23R expression and for stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. A serine-threonine kinase homologous to AKT4, SGK1 has been associated with cell cycle and apoptosis, and has been shown to govern Na+ transport and homeostasis5, 6 7, 8. We here show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is a critical regulator for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation. Th17 cells; comparing Sgk1-/- to WT

2013-03-07 | E-GEOD-43956 | biostudies-arrayexpress

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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

Effects of bromodomain inhibitors on CD4 T+ cells under Th17-promoting conditions

Project description:The human dataset includes the gene expression profile of CD4+ T cells isolated from blood of healthy controls and plated on TCP in RPMI-1640 containing 10% FCS, Penicillin-Streptomycin (50,000 units-50 mg) and L-glutamine (2 mM). Cells were stimulated for 4 days with 20 ng/ml of IL-1beta, 100 IU/ml of IL-2, 20 ng/ml of IL-6, 20 ng/ml IL-23 plus anti-CD2/3/28 beads at a ratio of 1 bead per 10 cells. RNA samples were isolated using the RNeasy Mini Kit (Qiagen) with on-column DNA digestion. The transcriptional profile was evaluated in three different donors using the HT12v4.1 BeadChip arrays from Illumina. Total RNA obtained from CD4+ T cells exposed to Th17-promoting cytokines.

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Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-β Signaling: ChIPSeq

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