2025年12月9日出版的《免疫学》杂志发表了中国科学家的一项最新成果。来自上海交通大学医学院的王锋小组的研究显示，TCR-SUB1-DOCK2轴通过驱动致病性CD4⁺ T细胞组织浸润来促进自身免疫。

研究小组发现转录因子SUB1在自身免疫性疾病患者的CD4⁺ T细胞中选择性上调。SUB1表达由T细胞受体(TCR)-干扰素调节因子4 （IRF4）转录因子轴诱导。T细胞中条件缺失Sub1可降低迁移调节因子DOCK2的表达，抑制rac依赖性肌动蛋白聚合和T细胞运动，防止实验性自身免疫性脑脊髓炎的发生。从机制上讲，SUB1经过液-液相分离形成生物分子凝聚物，在Junb和Dock2位点打开染色质。然后它直接反式激活Junb转录，并与Junb合作扩增Dock2转录。因此，SUB1是致病性T细胞运输的关键守门者，通过将TCR信号与细胞骨架重塑联系起来，TCR-SUB1- DOCK2轴成为自身免疫性疾病中易于处理的、以迁移为重点的治疗靶点。

据介绍，活化的CD4⁺ T细胞异常组织浸润是自身免疫的核心驱动因素，然而控制抗原特异性T细胞进入的分子检查点仍然不明确。

附：英文原文

Title: The TCR-SUB1-DOCK2 axis promotes autoimmunity by driving pathogenic CD4+ T cell tissue infiltration

Author: Xiaoxue Li, Wenhua Liang, Weifang Wang, Eilon Sherman, Keling Huang, Feng Wang

Issue&Volume: 2025-12-09

Abstract: Aberrant tissue infiltration by activated CD4+ T cells is a central driver of autoimmunity, yet the molecular checkpoints governing antigen-specific T cell ingress remain poorly defined. We found that the transcription factor SUB1 was selectively upregulated in CD4+ T cells from individuals with autoimmune diseases. SUB1 expression was induced by the T cell receptor (TCR)-interferon regulatory factor 4 (IRF4) transcription factor axis. Conditional deletion of Sub1 in T cells reduced the expression of migration regulator dedicator of cytokinesis 2 (DOCK2), inhibited Rac-dependent actin polymerization and T cell motility, and prevented the onset of experimental autoimmune encephalomyelitis. Mechanistically, SUB1 underwent liquid-liquid phase separation to form biomolecular condensates that opened chromatin at the Junb and Dock2 loci. It then directly trans-activated Junb transcription and partnered with JUNB to amplify Dock2 transcription. Therefore, SUB1 is a critical gatekeeper of pathogenic T cell trafficking, and by linking TCR signaling to cytoskeletal remodeling, the TCR-SUB1-DOCK2 axis emerges as a tractable, migration-focused therapeutic target in autoimmune disorders.

DOI: 10.1016/j.immuni.2025.11.009

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00511-4