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 severe pancreatitis. Female mice, in addition, are infertile and suffer from hysterosalpingitis. Tissue destruction is accompanied by infiltration with Mac-1 (CD11b)-positive monocytes/macrophages, Mac-1-positive T cells, and expansion of CD8+ T cells. In vivo inactivation of monocytes/macrophages by carrageenan reverses disease progression and restores fertility of female mice. Perforin/Fas-ligand double-deficient CD4+ or CD8+ CTL are unable to lyse cognate-activated macrophages, and therefore are unable to mediate negative feedback regulation by lysis of APCs, thereby preventing further T cell activation. These studies demonstrate a novel role for perforin in homeostatic regulation of the immune response.
Spielman
J
J
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33136, USA.
Lee
R K
RK
Podack
E R
ER
D000818:Animals; D017951:Antigen Presentation; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002351:Carrageenan / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D004716:Endometritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053222:Fas Ligand Protein; D005246:Feedback; D005260:Female; D007247:Infertility, Female / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008262:Macrophage Activation / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000032:analysis; D008264:Macrophages / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000473:pathology; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011247:Pregnancy; D012488:Salpingitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000473:pathology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D002351:Carrageenan