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

iScience (May 2023)

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

Affiliations

Yunke Wang: 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; Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Hui Qin: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Dermatology, Shanghai Jiaotong University Ruijin Hospital, Shanghai, China
Yihua Cai: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Xu Chen: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hong Li: Functional Immunomics Core, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Diego Elias Montoya-Durango: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Chuanlin Ding: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Xiaoling Hu: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Julia H. Chariker: Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, USA; Kentucky Biomedical Research Infrastructure Network Bioinformatics Core University of Louisville, Louisville, KY, USA
Harshini Sarojini: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Sufan Chien: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Eric C. Rouchka: Kentucky Biomedical Research Infrastructure Network Bioinformatics Core University of Louisville, Louisville, KY, USA; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA
Huang-Ge Zhang: Department of Microbiology and Immunology, Brown Cancer Center, University of Louisville, Louisville, KY, USA
Jie Zheng: Department of Dermatology, Shanghai Jiaotong University Ruijin Hospital, Shanghai, China
Fuming Qiu: Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Jun Yan: Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA; Corresponding author

Journal volume & issue: Vol. 26, no. 5
p. 106630

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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