Natural gamma delta T17 cell development and functional acquisition is governed by the mTORC2-c-Maf- controlled mitochondrial fission pathway

Natural IL-17-producing gamma delta T cells (gamma delta T17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of gamma delta T17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of gamma delta T17 cells through regulating transcription factor c-Maf expres-sion. scRNA-seq data suggest that fetal and adult gamma delta T17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochon-drial membrane potential (DJm) loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracel-lular ATP levels by ATP-encapsulated liposome completely rescues gamma delta T17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in gamma delta T17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and gamma delta T17 thymic programming and functional acquisition.