Abstract
Granzymes (gzms) are key components of T-killer (Tc) cells believed to mediate pro-apoptotic activities. Recent evidence suggests that gzms also possess non-cytotoxic activities that contribute to host defense. In this study, we show that Tc cells from lymphocytic choriomeningitis virus (LCMV)-infected wild-type (wt) and gzm A/B-deficient mice express similar levels of gzmK protein, with both mouse strains efficiently controlling infection. GzmK, in recombinant form or secreted by ex vivo-derived LCMV-immune gzmAxB(-/-) Tc cells, lacks pro-apoptotic activity. Instead, gzmK induces primary mouse macrophages to process and secrete interleukin-1β, independent of the ATP receptor P2X(7). Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arenaviridae Infections / enzymology
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Arenaviridae Infections / immunology*
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Granzymes / deficiency
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Granzymes / genetics
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Granzymes / metabolism*
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Inflammation Mediators / metabolism
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Interleukin 1 Receptor Antagonist Protein / pharmacology
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Interleukin-1beta / metabolism
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Lymphocytic choriomeningitis virus* / drug effects
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Lymphocytic choriomeningitis virus* / genetics
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Receptors, Purinergic P2X7 / deficiency
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Receptors, Purinergic P2X7 / genetics
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Receptors, Purinergic P2X7 / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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T-Lymphocytes, Cytotoxic / enzymology
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T-Lymphocytes, Cytotoxic / immunology*
Substances
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Inflammation Mediators
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1beta
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Receptors, Purinergic P2X7
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Recombinant Proteins
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Granzymes