Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is a Death Receptor for Granzyme B during Cytotoxic T Cell–Induced Apoptosis

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 rece...

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Bibliographic Details
Published in:Cell 2000-10, Vol.103 (3), p.491-500
Main Authors: Motyka, Bruce, Korbutt, Gregory, Pinkoski, Michael J, Heibein, Jeffrey A, Caputo, Antonio, Hobman, Marita, Barry, Michele, Shostak, Irene, Sawchuk, Tracy, Holmes, Charles F.B, Gauldie, Jack, Bleackley, R.Chris
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Binding, Competitive - drug effects
Cell Transplantation
Cells, Cultured
Cytotoxicity, Immunologic - drug effects
Endocytosis - drug effects
Flow Cytometry
Graft Rejection - immunology
Graft Rejection - metabolism
granzyme B
Granzymes
Humans
In Situ Nick-End Labeling
insulin-like growth factor receptors
Jurkat Cells
Kidney - immunology
L Cells (Cell Line)
mannose 6-phosphate
Mannosephosphates - metabolism
Mannosephosphates - pharmacology
Mice
Mice, Inbred BALB C
Mice, SCID
perforin
Phosphoric Monoester Hydrolases - metabolism
Phosphorylation
Protein Binding - drug effects
Receptor, IGF Type 2 - antagonists & inhibitors
Receptor, IGF Type 2 - metabolism
Serine Endopeptidases - metabolism
Serine Endopeptidases - pharmacology
T-Lymphocytes, Cytotoxic - immunology
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)00140-9