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Published 8 November 2004. doi:10.1083/jcb.200406115
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 3, 457-468
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Article

 Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis

Julián Pardo1, Alberto Bosque1, Reina Brehm2, Reinhard Wallich3, Javier Naval1, Arno Müllbacher4, Alberto Anel1, and Markus M. Simon2

1 Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Zaragoza, Spain
2 Max-Planck-Institut für Immunbiologie, D-79108 Freiburg, Germany
3 Institut für Immunologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany
4 John Curtin School of Medical Research, Australian National University, Canberra ACT 0200, Australia

Correspondence to M.M. Simon: simon{at}immunbio.mpg.de

Purified cytolytic T lymphocyte (CTL) proteases granzyme (gzm)A and gzmB with sublytic dose of perforin (perf) initiate distinct proapoptotic pathways. Their physiological relevance in CTL-mediated target cell apoptosis is elusive. Using ex vivo virus-immune CD8+ T cells from mice deficient in perf, gzmA and/or gzmB, and the Fas-resistant EL4.F15 tumor target cell, we show that (a) CTL from gzmA–/– or gzmB–/– mice similarly induced early proapoptotic features, such as phosphatidyl serine (PS) exposure on plasma membrane, {Delta}{Psi}m loss, and reactive oxygen radical generation, though with distinct kinetics; (b) CTL from gzmA–/– but not from gzmB–/– mice activate caspase 3 and 9; (c) PS exposure induced by CTL from gzmA–/– or gzmB–/– mice is prevented, respectively, by caspase inhibitors or by reactive oxygen scavengers without interfering with target cell death; and (d) all gzm-induced apoptotic features analyzed depend critically on perf. Thus, perf is the principal regulator in CTL-mediated and gzm-facilitated intracellular processes. The ability of gzmA and gzmB to induce multiple independent cell death pathways may be the hosts response to circumvent evasion strategies of pathogens and tumors.

Abbreviations used in this paper: CML, cytotoxicity assay; CTL, cytotoxic T lymphocyte; DiOC6(3), 3,3-dihexyloxacarbocyanin; FasL, fas ligand; gzm, granzyme; HE, hydroxiethidine; NAC, N-acetylcysteine; NK, Natural Killer; perf, perforin; PI, propidium iodide; PS, phosphatidyl serine; ROS, reactive oxygen species.


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