Perforin/Fas-ligand double deficiency is associated with macrophage expansion and severe pancreatitis

We report that perforin/Fas-ligand double-deficient mice die early of sever e pancreatitis. Female mice, in addition, are infertile and suffer from hys terosalpingitis, Tissue destruction is accompanied by infiltration with Mac -1 (CD11b)-positive monocytes/ macrophages, Mac-1-positive T cells, and exp ansion of CD8(+) T cells. In vivo inactivation of monocytes/macrophages by carrageenan reverses disease progression and restores fertility of female m ice. Perforin/Fas-ligand double-deficient CD4(+) or CD8(+) CTL are unable t o lyse cognate-activated macrophages, and therefore are unable to mediate n egative feedback regulation by lysis of APCs, thereby preventing further T cell activation. These studies demonstrate a novel role for perforin in hom eostatic regulation of the immune response.