Bai Ziran, Ren Jinyi, Liu Jiaqing, Zhang Cheng, Huang Huina, Zhao Xiangge, Chen Xianmei, Wei Jing, Qi Jingjing, Yang Siwen, Li Weiping, Tang Yawei, Wang Guan, Li Xia
Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, China.
Department of Hematology, the Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
Redox Biol. 2025 Aug 9;86:103818. doi: 10.1016/j.redox.2025.103818.
T cell senescence occurs in patients with rheumatoid arthritis (RA), but the specific phenotype and its contribution to tissue-destructive inflammation remain unclear. Here, we aim to investigate whether PD-1 marks pathogenic senescent CD4T cells and to explore the role and mechanism of senescent CD4PD-1T cells in RA pathogenesis. Here, we identified an expanded population of CD4PD-1T cells in RA patients that exhibited hallmark senescence features, including elevated senescence-associated secretory phenotype (SASP) production. Adoptive transfer experiments demonstrated that CD4PD-1T cells significantly accelerated disease progression in collagen-induced arthritis (CIA) models. Mechanistically, we demonstrated that RA CD4PD-1T cells showed decreased expression of dynamin-related protein 1 (DRP1) and impaired mitophagy, leading to mitochondrial reactive oxygen species (MtROS) accumulation and subsequent SASP production. Importantly, PD-1 signaling transcriptionally suppressed DRP1 expression through hypoxia inducible factor 1 alpha subunit (HIF-1α) inhibition. Our findings establish CD4PD-1T cells as a pathogenic senescent subset that drives RA progression through a PD-1-DRP1-mitophagy-SASP axis.
类风湿关节炎（RA）患者会发生T细胞衰老，但具体表型及其对组织破坏性炎症的作用仍不清楚。在此，我们旨在研究程序性死亡受体1（PD-1）是否标记致病性衰老的CD4+T细胞，并探讨衰老的CD4+PD-1+T细胞在RA发病机制中的作用和机制。在此，我们在RA患者中鉴定出一群扩增的CD4+PD-1+T细胞，其表现出衰老的标志性特征，包括衰老相关分泌表型（SASP）产物增加。过继转移实验表明，CD4+PD-1+T细胞显著加速了胶原诱导性关节炎（CIA）模型中的疾病进展。从机制上讲，我们证明RA患者的CD4+PD-1+T细胞中发动蛋白相关蛋白1（DRP1）表达降低且线粒体自噬受损，导致线粒体活性氧（MtROS）积累及随后的SASP产生。重要的是，PD-1信号通过抑制缺氧诱导因子1α亚基（HIF-1α）转录抑制DRP1表达。我们的研究结果确定CD4+PD-1+T细胞是一个致病性衰老亚群，其通过PD-1-DRP1-线粒体自噬-SASP轴驱动RA进展。
