TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models.

Autor: Jiang Z; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang H; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang X; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Duo H; Research Group of Computational and Integrative Biology, College of Life Sciences, Chongqing Normal University, Chongqing, China., Tao Y; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li J; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li X; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Liu J; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Ni J; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wu EJ; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Xiang H; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Guan C; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang X; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhang K; Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhang P; Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Hou Z; Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Liu Y; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China., Wang Z; Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Su B; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li B; Research Group of Computational and Integrative Biology, College of Life Sciences, Chongqing Normal University, Chongqing, China., Hao Y; Research Group of Computational and Integrative Biology, College of Life Sciences, Chongqing Normal University, Chongqing, China., Li B; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wu X; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Oct 31. Date of Electronic Publication: 2024 Oct 31.
DOI: 10.1172/JCI179874
Abstrakt: Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining regulatory T cells (Treg) stability and function, yet the underlying mechanism remains largely unexplored. Here we demonstrate that ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) Treg-specific knockout (Tmed4ΔTreg) mice contain more Treg cells with impaired Foxp3 stability, Treg signature and suppressive activity, which leads to T cell hyperactivation, exacerbated inflammatory phenotype and boosted anti-tumor immunity in mice. Mechanistically, loss of Tmed4 causes defects in ERS and nuclear factor erythroid 2-related factor 2 (NRF2)-related antioxidant response, which results in excessive reactive oxygen species (ROS) that reduces Foxp3 stability and suppressive function of Treg cells in an IRE1α-XBP1 axis-dependent manner. The abnormalities can be effectively rescued by ROS scavenger, NRF2 inducer or forcible expression of IRE1α. Moreover, TMED4 suppresses IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including BIP. Our study reveals that TMED4 maintains Treg cell stability and suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.
Databáze: MEDLINE