Anti-apoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells

Foxp3 + regulatory T (T reg ) cells are a crucial immunosuppressive population of CD4 + T cells, yet the homeostatic processes and survival programs that maintain the T reg cell pool are poorly understood. Here we report that peripheral T reg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2–dependent and costimulation-dependent process. By contrast, excess T reg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-x L and Bcl-2 were dispensable for survival of T reg cells, whereas Mcl-1 was critical for survival of T reg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which T reg cells maintain homeostasis via critical survival pathways.