Classic regulatory T (T_reg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of T_reg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as ‘the T_reg paradox’, we provide an overview of T_reg cell biology with a focus on T_reg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of T_reg cells while also promoting the differentiation of T_H17-like T_reg cell, exT_reg cell (effector T cells that were formerly T_reg cells), and osteoclastogenic T_reg cell subsets that mediate tissue injury. We present a new framework to understand T_reg cells in joint inflammation and define potential strategies for T_reg cell-directed interventions in human inflammatory arthritis.

表达 CD4 和标志性转录因子 FOXP3 的经典调节性 T （T_reg） 细胞是预防多系统自身免疫不可或缺的一部分。然而，免疫介导的关节炎通常与发炎关节中 T_reg 细胞数量的增加有关。为了理解这些看似相互矛盾的观察结果，我们将其统称为“T_reg 悖论”，我们提供了 T_reg 细胞生物学的概述，重点是 T_reg 细胞的异质性、功能和关节炎功能障碍。我们讨论了发炎环境如何限制 T_reg 细胞的免疫抑制活性，同时也促进 T_H17 样 T_reg 细胞、exT_reg 细胞（以前是 T_reg 细胞的效应 T 细胞）和介导组织损伤的破骨细胞_{T reg} 细胞亚群的分化。我们提出了一个新的框架来了解关节炎症中的 T_reg 细胞，并定义了 T_reg 细胞定向干预人类炎症性关节炎的潜在策略。