TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models
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
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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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 8

Tmed4 deficiency in Tregs leads to lower Foxp3 expression and ROS accumulation in an IRE1α/XBP1 axis–dependent manner.

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Tmed4 deficiency in Tregs leads to lower Foxp3 expression and ROS accum...
(A and B) Expression levels of Foxp3 (A) and cellular ROS (B) in WT splenic Tregs treated with α-CD3/α-CD28 antibodies (TCR) and 1 μM TG and the IRE1α inhibitor 4μ8C or KIRA6 for 16–20 hours (n = 3). (C and D) Quantitative analysis of the MFI of Foxp3 expression (C) and ROS (D) in WT and Tmed4-deficient splenic Tregs without (Ctrl) or with induced IRE1α expression. Cells were treated with 1 μM TG for 16–20 hours (n = 3). (E and F) FCM results (E) and statistical analysis (F) of the in vitro suppressive assay of purified Tregs from spleens of Tmed4fl/fl and Tmed4ΔTreg mice or Tmed4ΔTreg mouse splenic Tregs with forcible expression of IRE1α (Tmed4ΔTreg + IRE1α), as assessed by the proliferation of activated CD4+ T cells at various Treg ratios (Tresp/Treg = 4:2 and 4:1). n = 3, detected on day 3. (G) Western blot analysis of PERK expression and its downstream proteins in Ern1fl/fl (W) and Ern1ΔTreg (K) Tregs treated with DMSO or α-CD3/α-CD28 antibodies, alone or together with 1 μM TG, for 16–20 hours. 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 < 0.0001, by 1-way ANOVA with Tukey’s multiple-comparison test (A–D and F).