Published 10 April 2006. doi:10.1083/jcb.200510072
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 1, 133-144
Cytotoxic T lymphocyte–induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforin-dependent lysis
Nigel J. Waterhouse1,2,
Vivien R. Sutton1,
Karin A Sedelies1,
Annette Ciccone1,
Misty Jenkins3,
Stephen J. Turner3,
Phillip I. Bird4, and
Joseph A. Trapani1,2,3
1 Cancer Cell Death Laboratory, Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia
2 Department of Pathology, Faculty of Medicine, and 3 Department of Microbiology and Immunology, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia
4 Department of Biochemistry and Molecular Biology, Monash University, Clayton 3600, Australia
Correspondence to Nigel J. Waterhouse: nigel.waterhouse{at}petermac.org
Cytotoxic T lymphocyte (CTL)–induced death triggered by the granule exocytosis pathway involves the perforin-dependent delivery of granzymes to the target cell. Gene targeting has shown that perforin is essential for this process; however, CTL deficient in the key granzymes A and B maintain the ability to kill their targets by granule exocytosis. It is not clear how granzyme AB–/– CTLs kill their targets, although it has been proposed that this occurs through perforin-induced lysis. We found that purified granzyme B or CTLs from wild-type mice induced classic apoptotic cell death. Perforin-induced lysis was far more rapid and involved the formation of large plasma membrane protrusions. Cell death induced by granzyme AB–/– CTLs shared similar kinetics and morphological characteristics to apoptosis but followed a distinct series of molecular events. Therefore, CTLs from granzyme AB–/– mice induce target cell death by a unique mechanism that is distinct from both perforin lysis and apoptosis.
Abbreviations used in this paper: CTL, cytotoxic T lymphocyte; PI, propidium iodide; PS, phosphatidylserine.
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