Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function

Minghui Xia; Cai Zhang; Yufei Chen; Xiujuan Zhao; Si Zhang; Yang Liu; You Cai; Zhengping Wei; Qiuyang Du; Wenting Yu; Chun Zhou; Hongjun Xiao; Guihua Wang; Xiang Cheng; Heng Mei; Arian Laurence; Jing Wang; Yu Hu; Huabin Li; Xiang-Ping Yang

doi:10.1073/pnas.2205469119

Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function

Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2205469119. doi: 10.1073/pnas.2205469119. Epub 2022 Jul 27.

Authors

Minghui Xia¹, Cai Zhang^{1

2}, Yufei Chen¹, Xiujuan Zhao¹, Si Zhang³, Yang Liu¹, You Cai¹, Zhengping Wei¹, Qiuyang Du¹, Wenting Yu^{4

5}, Chun Zhou⁵, Hongjun Xiao⁴, Guihua Wang⁶, Xiang Cheng³, Heng Mei⁷, Arian Laurence⁸, Jing Wang¹, Yu Hu⁷, Huabin Li^{4

5}, Xiang-Ping Yang¹

Affiliations

¹ Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
² Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
³ Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
⁴ Department of Otolaryngology-Head and Neck Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
⁵ Allergy Center, Department of Otolaryngology, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, 200031, China.
⁶ GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
⁷ Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
⁸ Department of Hematology, University College London Hospitals NHS Trust, London, NW1 2BU, UK.

Abstract

T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4⁺ T cells. The loss of TFEB in Treg cells leads to reduced Treg accumulation and impaired Treg function in mouse models of cancer and autoimmune disease. TFEB intrinsically regulates genes involved in Treg cell differentiation and mitochondria function while it suppresses expression of proinflammatory cytokines independently of its established roles in autophagy. This coordinated action is required for mitochondria integrity and appropriate lipid metabolism in Treg cells. These findings identify TFEB as a critical regulator for orchestrating Treg generation and function, which may contribute to the adaptive responses of T cells to local environmental cues.

Keywords: Myc; TFEB; Treg; mTORC1; mitochondrial.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Physiological* / genetics
Adaptation, Physiological* / physiology
Animals
Autoimmune Diseases / immunology
Autophagy / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / physiology
Disease Models, Animal
Interleukin-2 / metabolism
Mice
Mitochondria* / genetics
Mitochondria* / metabolism
Neoplasms* / immunology
T-Lymphocytes, Regulatory* / immunology
Xenograft Model Antitumor Assays

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Interleukin-2
Tcfeb protein, mouse