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.