Immune “checkpoint” inhibitor antibodies have revolutionised cancer therapy. Checkpoint inhibitors primarily block inhibitory pathways in tumour-resident T cells, however interest in manipulating other effector populations, such as regulatory T (Treg) cells is growing. Targeting the potent immunosuppressive properties of FOXP3+regulatory T (Treg) cells has significant therapeutic potential. Yet, the molecular mechanisms controlling Treg cell homeostasis, particularly in disease settings, remain unclear.
We report that caspase-8 is a central regulator of Treg cell homeostasis in a context specific manner that is distinct from conventional T cells. Mouse genetic models showed that targeting caspase-8 in Treg cells could enhance elimination of viral infections (lymphocytic choriomeningitis), parasitic infections (Leishmania) and cancer (MC38). The loss of caspase-8-deficient Treg cells was rescued by genetic ablation of MLKL, a key regulator of the necroptotic cell death pathway. Mechanistically, the switch in caspase-8 function induced by inflammation was dependent on type I interferons upregulating MLKL in Treg cells.
Importantly, we found that inhibition of caspase-8 with a clinical stage compound revealed that human Treg cells have heightened sensitivity to necroptosis compared to conventional T cells. These findings reveal a fundamental mechanism in Treg cells that can be targeted for therapeutic benefit.