Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes.
Analysis of perforin-deficient mice has identified the cytolytic pathway and perforin as the preeminent effector molecule in T cell-mediated control of virus infections. In this paper, we show that mice lacking both granzyme A (gzmA) and granzyme B (gzmB), which are, beside perforin, key constituents of cytolytic vesicles, are as incapable as are perforin-deficient mice of controlling primary infections by the natural mouse pathogen ectromelia, a poxvirus. Death of gzmAxgzmB double knockout mice occurred in a dose-dependent manner, despite the expression of functionally active perforin and the absence of an intrinsic defect to generate splenic cytolytic T cells. These results establish that both gzmA and gzmB are indispensable effector molecules acting in concert with perforin in granule exocytosis-mediated host defense against natural viral pathogens.
Müllbacher
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Division of Immunology, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia. arno.mullbacher@anu.edu.au
Waring
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Stehle
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D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002859:Chromium Isotopes; D003602:Cytotoxicity, Immunologic; D004481:Ectromelia virus / Q000276:immunology*; D004482:Ectromelia, Infectious / Q000276:immunology*; D005260:Female; D053804:Granzymes; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D008099:Liver / Q000473:pathology / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000473:pathology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
D002859:Chromium Isotopes; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C509212:GZMA protein, human