Abstract
The serine proteinase granzyme B is crucial for the rapid induction of target cell apoptosis by cytotoxic T cells. Granzyme B was recently demonstrated to enter cells in a perforin-independent manner, thus predicting the existence of a cell surface receptor(s). We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (CI-MPR). Inhibition of the granzyme B-CI-MPR interaction prevented granzyme B cell surface binding, uptake, and the induction of apoptosis. Significantly, expression of the CI-MPR was essential for cytotoxic T cell-mediated apoptosis of target cells in vitro and for the rejection of allogeneic cells in vivo. These results suggest a novel target for immunotherapy and a potential mechanism used by tumors for immune evasion.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Binding, Competitive / drug effects
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Cell Transplantation
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Cells, Cultured
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Cytotoxicity, Immunologic / drug effects
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Endocytosis / drug effects
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Flow Cytometry
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Graft Rejection / immunology
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Graft Rejection / metabolism
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Granzymes
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Humans
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In Situ Nick-End Labeling
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Jurkat Cells
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Kidney / immunology
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L Cells
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Mannosephosphates / metabolism
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Mannosephosphates / pharmacology
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Mice
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Mice, Inbred BALB C
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Mice, SCID
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Phosphoric Monoester Hydrolases / metabolism
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Phosphorylation
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Protein Binding / drug effects
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Receptor, IGF Type 2 / antagonists & inhibitors
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Receptor, IGF Type 2 / metabolism*
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Serine Endopeptidases / metabolism*
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Serine Endopeptidases / pharmacology*
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T-Lymphocytes, Cytotoxic / immunology*
Substances
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Mannosephosphates
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Receptor, IGF Type 2
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mannose-6-phosphate
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Phosphoric Monoester Hydrolases
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GZMB protein, human
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Granzymes
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Gzmb protein, mouse
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Serine Endopeptidases