在肿瘤和自身免疫小鼠模型中,TMED4通过ROS平衡促进Treg抑制功能。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-31 DOI:10.1172/JCI179874
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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引用次数: 0

摘要

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起着至关重要的作用,但其潜在机制在很大程度上仍未得到探索。在这里,我们证明了ERS相关蛋白跨膜p24转运蛋白4(TMED4)Treg特异性敲除(Tmed4ΔTreg)小鼠含有更多的Treg细胞,其Foxp3稳定性、Treg特征和抑制活性受损,从而导致小鼠T细胞过度活化、炎症表型恶化和抗肿瘤免疫力增强。从机理上讲,Tmed4的缺失会导致ERS和核因子红细胞2相关因子2(NRF2)相关的抗氧化反应缺陷,从而导致过量的活性氧(ROS),以IRE1α-XBP1轴依赖的方式降低Foxp3的稳定性和Treg细胞的抑制功能。ROS清除剂、NRF2诱导剂或IRE1α的强制表达可有效地挽救这些异常。此外,TMED4还能通过包括BIP在内的ER相关降解(ERAD)系统抑制IRE1α蛋白体降解。我们的研究揭示了TMED4通过IRE1α依赖的ROS和NRF2相关的抗氧化反应维持Treg细胞的稳定性和抑制功能。
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TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models.

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.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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