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

• DOI: 10.1073/pnas.2205469119
• Publication Date: 2022-07-27T17:39:42Z
• Authors: 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
• Keywords: 0303 health sciences; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biological Sciences; Adaptation, Physiological; T-Lymphocytes, Regulatory; Xenograft Model Antitumor Assays; Autoimmune Diseases; Mitochondria; Disease Models, Animal; Mice; 03 medical and health sciences; Neoplasms; Autophagy; Animals; Interleukin-2

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.