Wang Yunke, Qin Hui, Cai Yihua, Chen Xu, Li Hong, Montoya-Durango Diego Elias, Ding Chuanlin, Hu Xiaoling, Chariker Julia H, Sarojini Harshini, Chien Sufan, Rouchka Eric C, Zhang Huang-Ge, Zheng Jie, Qiu Fuming, Yan Jun
Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA.
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
iScience. 2023 Apr 10;26(5):106630. doi: 10.1016/j.isci.2023.106630. eCollection 2023 May 19.
Natural IL-17-producing γδ T cells (γδT17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of γδT17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of γδT17 cells through regulating transcription factor c-Maf expression. scRNA-seq data suggest that fetal and adult γδT17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochondrial membrane potential () loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracellular ATP levels by ATP-encapsulated liposome completely rescues γδT17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in γδT17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and γδT17 thymic programming and functional acquisition.
天然产生白细胞介素-17的γδT细胞（γδT17细胞）是一类非常规的固有样T细胞，在胎儿胸腺中经历功能编程。然而，γδT17细胞发育的内在代谢机制仍不清楚。在此，我们证明，是mTORC2而非mTORC1通过调节转录因子c-Maf的表达来选择性地控制γδT17细胞的功能命运决定。单细胞RNA测序数据表明，胎儿和成年γδT17细胞主要利用线粒体代谢。mTORC2缺陷导致动力相关蛋白1（Drp1）介导的线粒体分裂受损以及线粒体功能障碍，其特征为线粒体膜电位丧失、氧化磷酸化（OXPHOS）减少以及随后的ATP耗竭。使用Drp1抑制剂Mdivi-1进行治疗可减轻咪喹莫特诱导的皮肤炎症。通过ATP包封脂质体重构细胞内ATP水平可完全挽救由mTORC2缺陷引起的γδT17细胞缺陷，揭示了代谢物ATP在γδT17细胞发育中的基本作用。这些结果深入洞察了线粒体OXPHOS途径与γδT17胸腺编程及功能获得之间的内在联系。
