Similar Datasets
Project description:CREB regulates Th17 cell development and function.
| PRJNA701056 | ENA
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:RORγt is well recognized as the lineage defining transcription factor for TH17 cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development and autoimmunity remain poorly understood. Here we demonstrate that the transcriptional repressor REV-ERBa is exclusively expressed in TH17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates TH17 cell development via repression of genes traditionally characterized as RORγt-dependent, including Il17a. Deletion of REV-ERBa enhanced TH17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed TH17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBa negatively regulates pro-inflammatory TH17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of TH17-mediated autoimmune diseases.
2018-12-19 | GSE122726 | GEO
Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation. Th17 cells have unique metabolic features, including a stem cell-like signature and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression). As a genetic model system we employ Th17 specific deletion of optic atrophy 1 (OPA1), a gene that encodes a protein involved in mitochondrial inner membrane fusion and cristae organization. As a result, we find that Th17 cells rely on mitochondrial fusion (due to their low metabolic activity). Here, we carry out DIA-based differential quantitative proteomic analysis of murine wild-type and OPA1 knock-out Th17 cells. Through Ingenuity pathway analysis and together with transcriptional and metabolomic profiling we identify the serine/threonine kinase liver associated kinase B1 (LKB1/STK11) as an essential node coupling mitochondrial function to IL-17A cytokine expression in T cells.
2022-10-13 | PXD036162 | Pride
Project description:REV-ERBa regulates TH17 cell development and autoimmunity
| PRJNA506082 | ENA
Project description:Adenylate cyclase signaling pathway is suggested to be a key regulator of immune system functions. However, specific effects of cyclic adenosine monophosphate on T helper cell differentiation and functions are unclear. Involvement of cAMP in Th cell differentiation program, in particular development of Th1, Th2, and Th17 subsets, was evaluated employing forskolin (FSK), a labdane diterpene well known as AC activator.
2022-12-14 | GSE220589 | GEO
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
Project description:scRNAseq analysis of forskolin effect on Th1, Th2 and Th17 differentiation
| PRJNA910476 | ENA
Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.
2020-03-25 | PXD016633 | Pride
Project description:The differentiation of Th17 cells is controlled by a complex network of transcription factors (TFs), including FOS and JUN proteins of the AP-1 family. The FOS-like proteins, FOSL1 and FOSL2 have recently been reported to control Th17 responses. The molecular mechanisms dictating their roles, however, are unclear. Moreover, although the functions of AP-1 TFs are largely governed by their protein-protein interactions, these are also poorly characterized in this milieu. Using affinity purification in combination with mass-spectrometry we established the first interactomes of FOSL1 and FOSL2 in human Th17 cells. In addition to their known interactions with JUN proteins, our analysis identified several novel binding partners of FOSL factors. Gene ontology analysis revealed RNA binding was enriched as the major functionality for FOSL1 and FOSL2 associated proteins, thereby suggesting possible mechanistic links that have not been studied before. Intriguingly, 29 interactors were found to be shared between FOSL1 and FOSL2, which included crucial regulators of Th17-fate. These findings, including unique and shared interactions, were validated using parallel reaction monitoring targeted mass-spectrometry (PRM-MS), with additional measurements with other laboratory methods. Overall, this study provides key insights into interaction-based signalling mechanisms of FOSL1 and FOSL2, which potentially control Th17 cell-development and associated pathologies.
2021-11-02 | PXD025729 | Pride