Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity [scRNA-seq]
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PROVIDER: PRJNA497860 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity
| PRJNA497854 | ENA
Project description:Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity [ATAC-seq]
| PRJNA497861 | ENA
Project description:TH17 cells in autoimmune disease are functionally and metabolically heterogeneous and contain a subset with stemness-associated features but lower anabolic metabolism and a reciprocal subset with higher metabolic activity that supports the transdifferentiation into TH1 cells.
2018-12-27 | GSE121598 | GEO
Project description:TH17 cells in autoimmune disease are functionally and metabolically heterogeneous and contain a subset with stemness-associated features but lower anabolic metabolism and a reciprocal subset with higher metabolic activity that supports the transdifferentiation into TH1 cells.
2018-12-27 | GSE121597 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-12-27 | GSE121599 | GEO
Project description:A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1-3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4-7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.
| S-EPMC6420879 | biostudies-literature
Project description:T-helper 17 (Th17) cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens, while also contributing to proinflammatory conditions and autoimmunity. While Transforming Growth Factor-beta 1 (TGFβ1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFβ3 and Activin in steering Th17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a TGFβ1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic Th17 cells. Analyses in both uveitis patients and an Experimental Autoimmune Uveitis (EAU) mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates IL-17A production under pathogenic Th17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by TGFβ1 signaling, is implicated in fatty acid metabolism pathways that favor non-pathogenic Th17 differentiation. Our drug screening identifies several FDA-approved compounds capable of upregulating Foxo1. Collectively, our findings offer compelling evidence that Foxo1 serves as a molecular switch to specifically control pathogenic versus non-pathogenic Th17 differentiation in a TGFβ1-dependent manner. These insights suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases, offering efficacy without compromising immune homeostasis.
2023-10-10 | GSE244599 | GEO
Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.
2020-05-26 | PXD010612 | Pride
Project description:Genome-wide analysis of Jarid2, Suz12, and c-Maf binding and H3K27me3 profiling in miR-155 KO and WT Th17 performed by ChIP-seq. We found that Jarid2 and c-Maf is differentially expressed in absence of miR-155 and they compete for binding to the Il22 promoter. We highlight targets of Jarid2 and Suz12 in miR-155 KO Th17 cells that are epigenetically silenced by increased H3K27me3 status. Furthermore, genome-wide analysis through Suz12 ChIP-exo in WT and Jarid2fl/fl;CD4cre Th17 reveals defects in PRC2 recruitment in abscence of Jarid2 that results in derepression of genes in Th17 cells. Thus, one main function of miR-155 is to curb epigenetic silencing by targeting Jarid2. Examination of Jarid2, Suz12, c-Maf binding and H3K27me3 changes in miR-155 KO and WT Th17.
2014-06-01 | E-GEOD-47528 | biostudies-arrayexpress
Project description:The early stages of human Th17 Cell differentiation were studied using label free proteomics to compare Th17 polarized CD4+ human T cells at 24 h and 72 h with activated cells (72 and 24 h) and Thp cells.
2019-01-28 | PXD008973 | Pride