1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in T _H 17 cells

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.

Fatty acid metabolism constrains Th9 cell differentiation and anti-tumor immunity via modulation of retinoic acid receptor signaling

“…Previously, we reported that extrinsic supplementation with fatty acids restored the function of Acaca ΔT Th17 cells, and improved the proliferation, survival, and metabolic reprogramming of TOFA-treated activated CD4 + T cells 17,26,31 . We therefore next sought to determine whether supplementation of fatty acids would cancel the differentiation induced in Th9 cells cultured under fatty acid-limited conditions.…”

“…ATAC-seq samples were prepared as described previously 74 . In short, 100,000 cells were pelleted and washed with 50 µL PBS, followed by treatment with 50 µL lysis buffer.…”

Plasma Lipidomic Profiling Using Mass Spectrometry for Multiple Sclerosis Diagnosis and Disease Activity Stratification (LipidMS)

“…The significantly altered lipids represent the typical distribution of polyunsaturated fatty acids in the sn2 position. Considering the cleavage products of PE, previous experiments with EAE mice demonstrated the requirement of LPE (1-18:1) for the activation of pathogenic Th17 cells [ 36 ]. In our study, we can attribute the significant change of this specific LPE to the RRMS course ( Figure 4 B).…”

179 Plasma lipids and risk of intracranial aneurysms: A genetic study of association and causality

“…These disorders of lipid metabolism may in uence the lipid deposition process in the aneurysm wall. Furthermore, recent investigations have reported that LPE (1-18:1) can regulate the differentiation of TH17 cells, a subset of proin ammatory T cells, by interacting with Retinoid-related orphan receptor gamma t (RORγt) [41] . Hence, further observational and basic research is needed to determine the precise underlying mechanisms of LPE in the development of IAs.…”