Caspase-8 Acts as a Molecular Rheostat to Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation

摘要

Caspase-8, an executioner enzyme in the death receptor pathway, has previously been shown to initiate apoptosis and suppress necroptosis. Here, we identify a novel, cell death-independent role for caspase-8 in dendritic cells (DCs); namely, DC-specific expression of caspase-8 prevents the onset of systemic autoimmunity. Failure to express caspase-8 has no effect on the life-span of DCs but instead leads to an enhanced intrinsic activation and subsequently more mature and autoreactive lymphocytes. Uncontrolled toll-like receptor activation in a RIPK1-dependent manner is responsible for the enhanced functionality of caspase-8-deficient DCs, as deletion of TLR signaling mediator, MyD88, ameliorates systemic autoimmunity induced by caspase-8 deficiency. Taken together, these data demonstrate that caspase-8 functions in a cell-type-specific manner and acts uniquely in DCs to maintain tolerance.