Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan.
Department of Omics Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana. Chuo-ku, Chiba 260-8670 Japan.
Sci Immunol. 2023 Aug 4;8(86):eadd4346. doi: 10.1126/sciimmunol.add4346.
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.
脂肪酸生物合成所涉及的代谢通量在调控辅助性 T 细胞 17（T17）细胞的分化中发挥着重要作用。然而，确切的酶和脂质代谢物，以及它们与促进 T17 细胞分化所需的核心基因转录特征的关系，在很大程度上仍然未知。通过基于 CRISPR 的 pooled 筛选和无偏脂质组学分析，我们发现 1-油酰基-溶血磷脂乙醇胺可作为 T17 细胞中视黄酸相关孤儿受体γ t（RORγt）活性的脂质调节剂。此外，我们鉴定了五个酶，包括、、、、和，提示需要具有单不饱和脂肪酸的甘油磷脂来转录。在缺乏的 T17 细胞中，1-油酰基-溶血磷脂乙醇胺减少，导致白细胞介素 17（IL-17）的产生被废除，并且破坏了 T17 细胞分化所需的核心转录程序。此外，在多发性硬化症的实验性自身免疫性脑脊髓炎模型中，T 细胞特异性缺乏的小鼠未能发展为疾病。因此，我们的数据表明 1-油酰基-溶血磷脂乙醇胺是一种促进 RORγt 诱导的 T17 细胞分化和 T17 细胞致病性的脂质代谢物。
