Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigen Presentation
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Autoimmune Diseases / drug therapy
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / pathology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Carrageenan / therapeutic use
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Cytotoxicity, Immunologic
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Endometritis / genetics
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Endometritis / immunology
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Endometritis / pathology
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Fas Ligand Protein
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Feedback
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Female
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Infertility, Female / drug therapy
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Infertility, Female / genetics
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Infertility, Female / immunology
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Infertility, Female / pathology
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Lymphocyte Activation
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Macrophage Activation* / drug effects
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Macrophage-1 Antigen / analysis
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Macrophages / pathology*
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasms, Experimental / pathology
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Pancreas / pathology
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Pancreatitis / genetics
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Pancreatitis / immunology
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Pancreatitis / pathology*
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Perforin
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Pore Forming Cytotoxic Proteins
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Pregnancy
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Salpingitis / genetics
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Salpingitis / immunology
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Salpingitis / pathology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / pathology*
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / pathology
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Tumor Cells, Cultured
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Uterus / pathology
Substances
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Fas Ligand Protein
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Fasl protein, mouse
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Macrophage-1 Antigen
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Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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Perforin
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Carrageenan