Jiang Zhenyan, Wang Huizi, Wang Xiaoxia, Duo Hongrui, Tao Yuexiao, Li Jia, Li Xin, Liu Jiamin, Ni Jun, Wu Emily Jiatong, Xiang Hongrui, Guan Chenyang, Wang Xinyu, Zhang Kun, Zhang Peng, Hou Zhaoyuan, Liu Yong, Wang Zhengting, Su Bing, Li Bo, Hao Youjin, Li Bin, Wu Xuefeng
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital.
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital.
J Clin Invest. 2024 Oct 31;135(1):e179874. doi: 10.1172/JCI179874.
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.
内质网应激（ERS）在维持调节性T细胞（Treg）的稳定性和功能方面发挥着关键作用，但其潜在机制在很大程度上仍未被探索。在此，我们证明，在Treg中特异性敲除ERS相关蛋白跨膜p24转运蛋白4（TMED4）的（Tmed4ΔTreg）小鼠，有更多Treg的叉头框蛋白3（Foxp3）稳定性受损、Treg特征及抑制活性受损，这导致T细胞过度活化和炎症表型加剧，并增强了小鼠的抗肿瘤免疫力。从机制上来说，Tmed4缺失导致ERS缺陷和核因子红细胞2相关因子2相关（NRF2相关）抗氧化反应缺陷，从而产生过量活性氧（ROS），以肌醇需求酶1α（IRE1α）/X盒结合蛋白1（XBP1）轴依赖的方式降低Treg的Foxp3稳定性和抑制功能。ROS清除剂、NRF2诱导剂或强制表达IRE1α可有效挽救这些异常。此外，TMED4通过包括内质网伴侣结合免疫球蛋白蛋白（BIP）在内的内质网相关降解（ERAD）系统抑制IRE1α蛋白酶体降解。我们的研究表明，TMED4通过IRE1α依赖的ROS和NRF2相关抗氧化反应维持Treg的稳定性及其抑制功能。
