Chai Timothy, Loh Kyle M, Weissman Irving L
Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
bioRxiv. 2024 Sep 24:2024.09.22.614388. doi: 10.1101/2024.09.22.614388.
T cell-targeted therapies are commonly used to manage T cell hyperactivity in autoimmune disorders, graft-versus-host diseases (GVHD), and transplant rejections. However, many patients experience significant side effects or inadequate responses to current treatments, highlighting the urgent need for alternative strategies. In this study, we searched for regulators of T cells through proximity labeling with APEX2 to detect proteins interacting with CD8α, a coreceptor of the T-cell receptor (TCR). This screen revealed TMX1, an ER resident transmembrane disulfide oxidoreductase, is essential for T cell cytotoxicity and NFAT, NFκB, and AP1 signaling but not cell proliferation. TMX1 deletion decreases surface TCR expression and destabilizes CD3ζ, a subunit of TCR complex; however, overexpression of CD3ζ rescues the phenotype, suggesting that TMX1 is not required for CD3ζ function. Mechanistically, TMX1 was found to directly engage the CxxC motif of CD3δ, which has been reported to be essential for proper TCR assembly and function. We hypothesize that the loss of TMX1 interaction with CD3δ leads to impaired TCR assembly and subsequent CD3ζ destabilization. These findings identify TMX1 as a novel regulator of T-cell receptor assembly and a potential target for immunosuppressive therapy.
T细胞靶向疗法常用于治疗自身免疫性疾病、移植物抗宿主病（GVHD）和移植排斥反应中的T细胞过度活跃。然而，许多患者对当前治疗有显著副作用或反应不足，这凸显了对替代策略的迫切需求。在本研究中，我们通过用APEX2进行邻近标记来寻找T细胞的调节因子，以检测与T细胞受体（TCR）的共受体CD8α相互作用的蛋白质。该筛选揭示了内质网驻留跨膜二硫键氧化还原酶TMX1对T细胞细胞毒性以及NFAT、NFκB和AP1信号传导至关重要，但对细胞增殖并非必需。TMX1缺失会降低表面TCR表达并使TCR复合物的亚基CD3ζ不稳定；然而，CD3ζ的过表达可挽救该表型，表明TMX1对CD3ζ功能并非必需。从机制上讲，发现TMX1直接与CD3δ的CxxC基序结合，据报道该基序对正确的TCR组装和功能至关重要。我们推测TMX1与CD3δ相互作用的丧失会导致TCR组装受损以及随后的CD3ζ不稳定。这些发现确定TMX1是T细胞受体组装的新型调节因子和免疫抑制治疗的潜在靶点。
