Caspase-8 has dual roles in regulatory T cell homeostasis balancing immunity to infection and collateral inflammatory damage.

Targeting the potent immunosuppressive properties of FOXP3+ regulatory T cells (Tregs) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling Treg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of Treg homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in Tregs led to accumulation of effector Tregs resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8-deficient lymphoid and tissue Tregs, which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human Tregs have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in Tregs that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.