The pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells of RA patients, with highly similar TCR repertoires. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Notably, we showed that TCR diversity and abundance of differentiated T cells of Th17 were significantly correlated with RA disease activity. Based on these observations, we propose that abnormal differentiation from EMT to Th17 and expansion of Th17 play pivotal role in RA pathogenesis.

中文翻译：

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类风湿性关节炎中 CD4+ T 细胞亚群的综合 TCR 谱分析。

类风湿性关节炎 (RA) 是一种以自身反应性 T 细胞积累和促炎细胞因子过度产生为特征的全身性自身免疫性疾病，其发病机制尚不清楚。系统地解决不同 CD4+ T 细胞亚群的 T 细胞受体 (TCR) 库可以帮助了解 RA 的发病机制。在这里，来自未经治疗的 RA 患者和健康对照的外周 CD4+ T 细胞被分为七个亚群，包括初始、效应、中枢记忆、效应记忆 (EMT)、Th1、Th17 和调节性 T 细胞。然后通过下一代测序分析 T 细胞受体 β 链库。我们在 RA 患者的 EMT 和 Th17 细胞中发现了 T 细胞克隆扩增，具有高度相似的 TCR 库。离体实验证明了 RA 中从 EMT 到 Th17 细胞的首选分化。尤其，我们发现 TCR 多样性和 Th17 分化 T 细胞的丰度与 RA 疾病活动显着相关。基于这些观察，我们提出从 EMT 到 Th17 的异常分化和 Th17 的扩增在 RA 发病机制中起关键作用。