Granzyme B: a natural born killer
Article first published online: 12 MAY 2003
Volume 193, Issue 1, pages 31–38, June 2003
How to Cite
Lord, S. J., Rajotte, R. V., Korbutt, G. S. and Bleackley, R. C. (2003), Granzyme B: a natural born killer. Immunological Reviews, 193: 31–38. doi: 10.1034/j.1600-065X.2003.00044.x
- Issue published online: 12 MAY 2003
- Article first published online: 12 MAY 2003
Summary: A main pathway used by cytotoxic T lymphocytes (CTLs) and natural killer cells to eliminate pathogenic cells is via exocytosis of granule components in the direction of the target cell, delivering a lethal hit of cytolytic molecules. Amongst these, granzyme B and perforin have been shown to induce CTL-mediated target cell DNA fragmentation and apoptosis. Once released from the CTL, granzyme B binds its receptor, the mannose-6-phosphate/insulin-like growth factor II receptor, and is endocytosed but remains arrested in endocytic vesicles until released by perforin. Once in the cytosol, granzyme B targets caspase-3 directly or indirectly through the mitochondria, initiating the caspase cascade to DNA fragmentation and apoptosis. Caspase activity is required for apoptosis to occur; however, in the absence of caspase activity, granzyme B can still initiate mitochondrial events via the cleavage of Bid. Recent work shows that granzyme B-mediated release of apoptotic factors from the mitochondria is essential for the full activation of caspase-3. Thus, granzyme B acts at multiple points to initiate the death of the offending cell. Studies of the granzyme B death receptor and internal signaling pathways may lead to critical advances in cell transplantation and cancer therapy.