title: Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation.
abstract: 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 determined. 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-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas(-/-) DCs induced over-activation and IFN-γ production in perforin(-/-) CD8+ T cells. Neutralization of IFN-γ 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.
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. minc@bcm.edu
authors: Min
authors: M
authors: Chen
authors: Kumar
authors: K
authors: Felix
authors: Jin
authors: J
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054353:Perforin / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology*
chemical_list: D016207:Cytokines; C491899:Fas protein, mouse; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma