Antiapoptotic 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.