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 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.
Motyka
B
B
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Korbutt
G
G
Pinkoski
M J
MJ
Heibein
J A
JA
Caputo
A
A
Hobman
M
M
Barry
M
M
Shostak
I
I
Sawchuk
T
T
Holmes
C F
CF
Gauldie
J
J
Bleackley
R C
RC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D017690:Cell Transplantation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D007668:Kidney / Q000276:immunology; D007739:L Cells; D008360:Mannosephosphates / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate; D010744:Phosphoric Monoester Hydrolases; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases