Decoupling the role of RORgt in the differentiation and effector function of Th17 cells
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PROVIDER: PRJNA870574 | ENA |
REPOSITORIES: ENA
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Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.
2022-10-26 | GSE211509 | GEO
Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.
2022-10-26 | GSE211414 | GEO
Project description:Decoupling the role of RORγt in the differentiation and effector function of Th17 cells
| PRJNA870149 | ENA
Project description:T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORgt. Here we identify REV-ERBa (encoded by Nr1d1), a member of the nuclear hormone receptor family (NHR), as a transcriptional repressor that antagonizes RORgt function in Th17 cells. REV-ERBa binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORgt-dependent genes such as Il17a and Il17f. Furthermore, elevated REV-ERBa expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated autoimmune disease. These results suggest that modulating REV-ERB activity may hold therapeutic potential for treatment of Th17 cell-mediated autoimmune diseases.
2019-08-16 | GSE72271 | GEO
Project description:Th17 cells are a helper cell subset of pro-inflammatory T cells, which have diverse functions ranging from neutrophilic-inflammatory responses against pathogens to driving a number of autoimmune diseases. Accumulating evidence indicates that specific cellular lipid metabolic pathways that include fatty acid or cholesterol play an essential role in regulating the differentiation and function of Th17 cells. However, what molecular mechanisms link lipid metabolism and RORgt function during Th17-cell differentiation? By using a combination of a CRISPR- based screening system and a global lipidome analysis, we addressed this question in an effort to identify a specific lipid metabolite that is essential for RORgt-mediated Th17-cell differentiation. We found five lipid enzymes that elicit RORgt activity and constitute a core molecular signature of Th17 cells. Furthermore, although Th17 cells treated with TOFA, which is a ACC1 inhibitor, showed decreased mRNA expression of Th17 specific gene and chromatin accessibility at Th17 cell specific gene loci, we also found that extrinsic supplementation of LPE (1-18:1) restored the phenotype of ACC1-inhibited Th17 cells. Taken together, these series of results indicated that LPE (1-18:1) synthesized from the five lipid metabolic enzymes was required for RORgt to function appropriately in Th17-cell differentiation.
2023-05-08 | GSE230624 | GEO
Project description:STAT3 has a more profound effect on chromatin accessibility regulation than RORgt during Th17 cell differentiation.
2020-07-30 | GSE153442 | GEO
Project description:An LKB1-mitochondria axis controls Th17 effector function
| PRJNA856302 | ENA
Project description:Role of JunB in Th17 cell effector stability
| PRJNA385018 | ENA
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 inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. 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) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.
2022-09-19 | GSE207602 | GEO
Project description:Purpose: The goals of this study are to compare RNAs bound by DDX5 and RORgt in cultured T helper 17 cell in wildtype background. Methods: Th17 mRNA profiles of 48hrs in vitro cultured T helper 17 cells from wild-type mice were generated by deep sequencing, using Illumina HighSeq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: BurrowsâWheeler Aligner (BWA) and TopHat followed by CuffDiff. qRTâPCR validation was performed using SYBR Green assays. Results: Among the 3444 RefSeq non-coding RNAs and 46449 NONCODE non-coding RNAs, 2533 were found to be expressed in Th17 cells (FPKM>1). 210 of them were enriched in DDX5 pull-down and 119 of them were enriched in RORgt pull-down. Conclusions: Our study suggest that a subset of 31 ncRNAs were co-enriched in DDX5 and RORgt pull-down. DDX5 or RORgt-associated-RNA profiles of 48hr in vitro cultured Th17 from wild type (WT) mice were generated by deep sequencing using Illumina HighSeq
2015-12-21 | E-GEOD-70109 | biostudies-arrayexpress