1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in T H 17 cells.

Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (T H 17) 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 T H 17 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 T H 17 cells. In addition, we specified five enzymes, including Gpam , Gpat3 , Lplat1 , Pla2g12a , and Scd2 , suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a . 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a -deficient T H 17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of T H 17 cells. Furthermore, mice with T cell-specific deficiency of Pla2g12a 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 T H 17 cell differentiation and the pathogenicity of T H 17 cells.