title: Cytotoxic T lymphocyte-induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforin-dependent lysis.
abstract: 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.
authors.affiliation: Cancer Cell Death Laboratory, Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia. nigel.waterhouse@petermac.org
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waterhouse
authors.forename: Vivien R
authors.initials: VR
authors.lastname: Sutton
authors.forename: Karin A
authors.initials: KA
authors.lastname: Sedelies
authors.forename: Annette
authors.initials: A
authors.lastname: Ciccone
authors.forename: Misty
authors.initials: M
authors.lastname: Jenkins
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Bird
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D022081:Cell Surface Extensions / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism*; D053804:Granzymes; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases