1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in T17 cells.

Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (T17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of T17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in T17 cells. In addition, we specified five enzymes, including , , , , and , suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of . 1-Oleoyl-lysophosphatidylethanolamine was reduced in -deficient T17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of T17 cells. Furthermore, mice with T cell-specific deficiency of failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORγt-induced T17 cell differentiation and the pathogenicity of T17 cells.