RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3- and FADD-mediated cell death.

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.