Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis

Cell. 2000 Oct 27;103(3):491-500. doi: 10.1016/s0092-8674(00)00140-9.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Granzymes
  • Humans
  • In Situ Nick-End Labeling
  • Jurkat Cells
  • Kidney / immunology
  • L Cells
  • Mannosephosphates / metabolism
  • Mannosephosphates / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • 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*


  • Mannosephosphates
  • Receptor, IGF Type 2
  • mannose-6-phosphate
  • Phosphoric Monoester Hydrolases
  • GZMB protein, human
  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases