1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in T <sub>H</sub> 17 cells
Yusuke Endo, Toshio Kanno, Takahiro Nakajima, Kazutaka Ikeda, Yoshitaka Taketomi, Satoru Yokoyama, S. Sasamoto, Hikari K. Asou, Keisuke Miyako, Yoshinori Hasegawa, Yusuke Kawashima, Osamu Ohara, Makoto Murakami, Toshinori Nakayama
Abstract
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.