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 3

Loss of Tmed4 in Tregs leads to a more exacerbated inflammatory phenotype in mice.

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Loss of Tmed4 in Tregs leads to a more exacerbated inflammatory phenotyp...
(A) Mean clinical score for diseased Tmed4fl/fl and Tmed4ΔTreg mice (n = 4). (B) FCM analysis of CD4+ and CD8+ T cell proportions isolated from the CNS of diseased Tmed4fl/fl and Tmed4ΔTreg mice 16 days after disease induction (n = 4). (C) H&E and LFB stainings of spinal cord sections from diseased Tmed4fl/fl and Tmed4ΔTreg mice (16 days after immunization). Scale bars: 100 μm. Samples were selected from 1 Tmed4fl/fl mouse (clinical score: 1) and 1 Tmed4ΔTreg mouse (clinical score: 3). (D and E) FCM analysis of Treg frequencies (D) and Foxp3 MFI (E) in dLNs and CNS (n = 4). (F and G) FCM analysis of (F) IFN-γ–producing CD4+ and CD8+ T cells from spleens, dLNs, and CNS and (G) IL-17–producing CD4+ T cells from dLNs and CNS from diseased Tmed4fl/fl and Tmed4ΔTreg mice (n = 4). (H) Curve for the percentage of body weight loss. Rag1–/– mice were injected with CD4+CD45RBhiCD25lo naive T cells alone or in combination with Tregs isolated from Tmed4fl/fl and Tmed4ΔTreg mice. The body weight is presented relative to the initial weight in each case (n = 3 for mice coinjected with naive T mixed Tmed4fl/fl or Tmed4ΔTreg Tregs, respectively; n = 2 for mice injected with naive T cells alone). (I) H&E staining of colon (Co) and small intestine (SI) after adoptive transfer. Scale bar: 100 μm. (J) Percentages of CD45+ cells infiltrating into the colon and small intestine (n = 3 for mice coinjected with naive T mixed WT or Tmed4-deficient Tregs, respectively; n = 2 for mice injected with naive T cells alone). Data are presented as the mean ± SEM of biologically independent samples and represent 3 independent experiments, each involving 2–4 mice per group. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA (A), 1-way ANOVA with Tukey’s multiple-comparison test (H), and 2-tailed Student’s t test for other analysis.