Regulatory T (T_reg) cells play an essential role in maintaining immune balance across various physiological and pathological conditions. However, the mechanisms underlying T_reg homeostasis remain incompletely understood. Here, we report that RIPK1 is crucial for T_reg cell survival and homeostasis. We generated mice with T_reg cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the T_reg cell compartment caused by excessive cell death. Unlike conventional T cells, T_reg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis. However, simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient T_reg cells by blocking two cell death pathways. Thus, our study highlights the critical role of RIPK1 in regulating T_reg cell homeostasis by controlling both apoptosis and necroptosis, thereby providing novel insights into the mechanisms of T_reg cell homeostasis.

调节性 T (T _reg ) 细胞在维持各种生理和病理条件下的免疫平衡中发挥着重要作用。然而，T _reg稳态的机制仍不完全清楚。在此，我们报告 RIPK1 对于 T _reg细胞的存活和稳态至关重要。我们培育了 T _reg细胞特异性消融Ripk1的小鼠，发现这些小鼠由于过度细胞死亡导致 T _reg细胞区室急剧减少而产生了致命的全身性自身免疫。与传统 T 细胞不同， Ripk1缺陷的 T _reg细胞通过阻断 FADD 依赖性细胞凋亡，只能部分地免于细胞死亡。然而，同时去除Fadd和Ripk3通过阻断两条细胞死亡途径，完全恢复了Ripk1缺陷的 T _reg细胞的稳态。因此，我们的研究强调了 RIPK1 通过控制细胞凋亡和坏死性凋亡在调节 T _reg细胞稳态中的关键作用，从而为 T _reg细胞稳态机制提供了新的见解。