Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

After stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be deter-mined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin(-/-) DC-Fas(-/-)), led to DC accumulation, uncontrolled T-cell activation, and IFN-gamma production by CD8(+) T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas(-/-) DCs induced over-activation and IFN-gamma production in perforin(-/-) CD8(+) T cells. Neutralization of IFN-gamma prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin(-/-) DC-Fas(-/-) mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade. (Blood. 2012; 119(1): 127-136)