Natural γδT17 cell development and functional acquisition is governed by the mTORC2- c-Maf-controlled mitochondrial fission pathway

Yunke Wang; Hui Qin; Yihua Cai; Xu Chen; Hong Li; Diego Elias Montoya-Durango; Chuanlin Ding; Xiaoling Hu; Julia H Chariker; Harshini Sarojini; Sufan Chien; Eric C Rouchka; Huang-Ge Zhang; Jie Zheng; Fuming Qiu; Jun Yan

doi:10.1016/j.isci.2023.106630

Natural γδT17 cell development and functional acquisition is governed by the mTORC2- c-Maf-controlled mitochondrial fission pathway

iScience. 2023 Apr 10;26(5):106630. doi: 10.1016/j.isci.2023.106630. eCollection 2023 May 19.

Authors

Yunke Wang^{1

2

3}, Hui Qin^{1

4}, Yihua Cai¹, Xu Chen^{1

5}, Hong Li⁶, Diego Elias Montoya-Durango¹, Chuanlin Ding¹, Xiaoling Hu¹, Julia H Chariker^{7

8}, Harshini Sarojini¹, Sufan Chien¹, Eric C Rouchka^{8

9}, Huang-Ge Zhang¹⁰, Jie Zheng⁴, Fuming Qiu^{2

3}, Jun Yan¹

Affiliations

¹ Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA.
² Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
⁴ Department of Dermatology, Shanghai Jiaotong University Ruijin Hospital, Shanghai, China.
⁵ Department of Clinical Immunology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Functional Immunomics Core, Brown Cancer Center, University of Louisville, Louisville, KY, USA.
⁷ Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, USA.
⁸ Kentucky Biomedical Research Infrastructure Network Bioinformatics Core University of Louisville, Louisville, KY, USA.
⁹ Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.
¹⁰ Department of Microbiology and Immunology, Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Abstract

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 (ΔΨm) 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.

Keywords: Cell biology; Immunology; Molecular biology; Molecular mechanism of gene regulation.

Grants and funding

R01 AI128818/AI/NIAID NIH HHS/United States