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

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 per...

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Main Authors: Pardo, Julián (Author) , Bosque, Alberto (Author) , Brehm, Reina (Author) , Wallich, Reinhard (Author) , Naval, Javier (Author) , Müllbacher, Arno (Author) , Anel, Alberto (Author) , Simon, Markus M. (Author)
Format: Article (Journal)
Language:English
Published: 2004
In: The journal of cell biology
Year: 2004, Volume: 167, Issue: 3, Pages: 457-468
ISSN:1540-8140
DOI:10.1083/jcb.200406115
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1083/jcb.200406115
Verlag, lizenzpflichtig, Volltext: https://rupress.org/jcb/article/167/3/457/51394
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Author Notes:Julián Pardo, Alberto Bosque, Reina Brehm, Reinhard Wallich, Javier Naval, Arno Müllbacher, Alberto Anel, and Markus M. Simon
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Summary: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.
Item Description:Gesehen am 24.02.2021
Physical Description:Online Resource
ISSN:1540-8140
DOI:10.1083/jcb.200406115

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