TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models
Zhenyan Jiang, … , Bin Li, Xuefeng Wu
Zhenyan Jiang, … , Bin Li, Xuefeng Wu
Published October 31, 2024
Citation Information: J Clin Invest. 2025;135(1):e179874. https://doi.org/10.1172/JCI179874.
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Research Article Immunology

TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models

Abstract

Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining Treg stability and function, yet the underlying mechanism remains largely unexplored. Here, we demonstrate that (Tmed4ΔTreg) mice with Treg-specific KO of ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) had more Tregs with impaired Foxp3 stability, Treg signatures, and suppressive activity, which led to T cell hyperactivation and an exacerbated inflammatory phenotype and boosted antitumor immunity in mice. Mechanistically, loss of Tmed4 caused defects in ERS and a nuclear factor erythroid 2–related factor 2–related (NRF2-related) antioxidant response, which resulted in excessive ROS that reduced the Foxp3 stability and suppressive function of Tregs in an IRE1α/XBP1 axis–dependent manner. The abnormalities could be effectively rescued by the ROS scavenger, NRF2 inducer, or by forcible expression of IRE1α. Moreover, TMED4 suppressed IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including the ER chaperone binding immunoglobulin protein (BIP). Our study reveals that TMED4 maintained the stability of Tregs and their suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.

Authors

Zhenyan Jiang, Huizi Wang, Xiaoxia Wang, Hongrui Duo, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Hongrui Xiang, Chenyang Guan, Xinyu Wang, Kun Zhang, Peng Zhang, Zhaoyuan Hou, Yong Liu, Zhengting Wang, Bing Su, Bo Li, Youjin Hao, Bin Li, Xuefeng Wu

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Figure 1

Treg-specific Tmed4-KO (Tmed4ΔTreg) mice exhibit T cell hyperactivation, and impaired Foxp3 stability in Tregs.

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Treg-specific Tmed4-KO (Tmed4ΔTreg) mice exhibit T cell hyperactivation,...
(A) Images of spleens and pLNs from 12-week-old sex-matched littermate Tmed4fl/fl (WT) mice and Tmed4ΔTreg (cKO) mice. (B) Spleen/body weight ratios of Tmed4fl/fl and Tmed4ΔTreg mice (n = 3). (C–E) FCM plots (C) and analysis (D and E) of effector CD4+ and CD8+ T cells isolated from spleens, pLNs, and lungs from Tmed4fl/fl and Tmed4ΔTreg mice (n = 3). (F and G) FCM plots (F) and analysis (G) of IFN-γ–producing CD4+ and CD8+ T cells from spleens and pLNs from Tmed4fl/fl and Tmed4ΔTreg mice (n = 3). (H and I) FCM plots (H) and analysis (I) of Treg frequencies in CD4+ T cells from spleens, pLNs, and lungs from Tmed4fl/fl and Tmed4ΔTreg mice (n = 3). (J) FCM analysis of Foxp3 MFI in Tregs from spleens, pLNs, and lungs from Tmed4fl/fl and Tmed4ΔTreg mice (n = 3). (K and L) FCM levels (K) and analysis (L) of Foxp3 MFI in iTregs (CD4+CD25+Foxp3+) generated in vitro 2 or 3 days after the naive T cells were purified and cultured with differentiation inducers (n = 3). (M and N) Western blotting (M) and quantitative analysis (N) of FOXP3 decay in WT and Tmed4-deficient Tregs purified from spleens and pLNs treated with 1 μg/mL CHX for the indicated durations. Data are presented as the mean ± SEM of biologically independent samples and represent at least 3 independent experiments, each involving 3 mice per group. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test. Sp, spleen.