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

Pardo, Julian; Bosque, Alberto; Brehm, R; Wallich, Reinhard; Naval, Javier; Mullbacher, Arno; Anel, A; Simon, Markus M

Description

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)...[Show more]

dc.contributor.authorPardo, Julian
dc.contributor.authorBosque, Alberto
dc.contributor.authorBrehm, R
dc.contributor.authorWallich, Reinhard
dc.contributor.authorNaval, Javier
dc.contributor.authorMullbacher, Arno
dc.contributor.authorAnel, A
dc.contributor.authorSimon, Markus M
dc.date.accessioned2015-12-13T22:38:13Z
dc.date.available2015-12-13T22:38:13Z
dc.identifier.issn0021-9525
dc.identifier.urihttp://hdl.handle.net/1885/77455
dc.description.abstractPurified 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, ΔΨm loss, and reactive oxygen radical generation, though with distinct kinetics; (b) CTL from gzmA-l- but not from gzmB-l- 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.
dc.publisherRockefeller University Press
dc.sourceJournal of Cell Biology
dc.subjectKeywords: benzyloxycarbonylaspartylglutamylvalylaspartyl fluoromethyl ketone; benzyloxycarbonylvalylalanylaspartyl fluoromethyl ketone; caspase 3; caspase 9; endonuclease; endonuclease ape 1; granzyme A; granzyme B; perforin; phosphatidylserine; reactive oxygen met
dc.titleApoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume167
dc.date.issued2004
local.identifier.absfor110799 - Immunology not elsewhere classified
local.identifier.ariespublicationMigratedxPub6316
local.type.statusPublished Version
local.contributor.affiliationPardo, Julian, Max Planck Institute of Immunobiology
local.contributor.affiliationBosque, Alberto, Universidad de Zaragoza
local.contributor.affiliationBrehm, R, Max Planck Institute of Immunobiology
local.contributor.affiliationWallich, Reinhard, Max Planck Institute of Immunobiology
local.contributor.affiliationNaval, Javier, Universidad de Zaragoza
local.contributor.affiliationMullbacher, Arno, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationAnel, A, Universidad de Zaragoza
local.contributor.affiliationSimon, Markus M, Max Planck Institute of Immunobiology
local.bibliographicCitation.issue3
local.bibliographicCitation.startpage457
local.bibliographicCitation.lastpage468
local.identifier.doi10.1083/jcb.200406115
dc.date.updated2016-02-24T09:48:48Z
local.identifier.scopusID2-s2.0-8444249247
CollectionsANU Research Publications

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