Affiliation:
1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX
Abstract
Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg–specific deletion of Traf3ip3 impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)–mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Mechanistically, TRAF3IP3 restricts mTORC1 signaling by recruiting the serine-threonine phosphatase catalytic subunit (PP2Ac) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Our results define TRAF3IP3 as a metabolic regulator in T reg cell stability and function and suggest a lysosome-specific mTORC1 signaling mechanism that regulates T reg cell metabolism.
Funder
Recruitment Program of Global Experts of China
National Natural Science Foundation of China
National Key Research and Development Program
Shanghai Rising-Star Program
Shanghai Municipal Commission of Health and Family Planning
Shanghai Jiao Tong University
Medical and Engineering Cross Research Foundation
U.S. National Institutes of Health
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy
Cited by
40 articles.
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