Abstract
Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8+ T cells. We report that CD8+ T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8+ T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8+ T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8+ T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8+ T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arenaviridae Infections / immunology
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Arenaviridae Infections / metabolism
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Arenaviridae Infections / virology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Chemokine CCL5 / metabolism
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Cytotoxicity, Immunologic / immunology*
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Female
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Granzymes / genetics
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Granzymes / metabolism
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Immunoblotting
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Immunological Synapses / immunology
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Lymphocytic choriomeningitis virus / physiology
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Male
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Mice
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Mice, Knockout
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Microscopy, Fluorescence
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Perforin / genetics
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Perforin / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Secretory Vesicles / enzymology
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Secretory Vesicles / metabolism*
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Sphingomyelin Phosphodiesterase / genetics
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Sphingomyelin Phosphodiesterase / metabolism*
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
Substances
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Chemokine CCL5
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Perforin
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acid sphingomyelinase-1
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Sphingomyelin Phosphodiesterase
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Granzymes