The effect of 1-Oleoyl-lysophosphatidylethanolamine (LPE) on the RORgt activity in Th17 cells
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. Overall design: Related to Fig 2,   RNA-seq was performed to investigate lipid synthesis genes which regulate differantiation of Th17 cells. Related to Fig 4.   RNA-seq was performed to investigate the role of LPE (1-18:1) on the regulation of Th17 cells specific gene expression. Related to Fig 5,   ATAC-seq was performed to investigate the role of LPE (1-18:1) on the chromatin accessibility at Th17 cell specific gene loci.