Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response (DDR) associated with cell death occur in Tregs in individuals with autoimmunity. In an experimental autoimmune encephalitis (EAE) mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature. Scavenging of mtROS in Tregs of EAE mice reversed the DDR and prevented Treg death, while attenuating the Th1 and Th17 autoimmune responses. These findings highlight an unrecognized role of mitochondrial oxidative stress in defining Treg fate during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance.

调节性 T 细胞 (Treg) 对于维持免疫稳态至关重要，而它们的功能障碍是自身免疫的一个主要特征。在稳态条件下，线粒体代谢对于 Treg 功能至关重要；然而，Tregs 在自身免疫过程中的代谢适应尚不清楚。在此，我们报告了自身免疫个体的 Tregs 中出现线粒体氧化应激升高和与细胞死亡相关的强烈 DNA 损伤反应 (DDR)。在实验性自身免疫性脑炎 (EAE) 小鼠模型中，我们发现 Treg 功能障碍，概括了具有显着 mtROS 特征的自身免疫性 Tregs 的特征。清除 EAE 小鼠 Tregs 中的 mtROS 可逆转 DDR 并防止 Treg 死亡，同时减弱 Th1 和 Th17 自身免疫反应。这些发现强调了线粒体氧化应激在定义自身免疫过程中 Treg 命运方面未被认识到的作用，这可能有助于设计针对免疫耐受受损疾病的新型免疫疗法。