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Perforin and Fas act together in the inductin of apoptosis, and both are critical in the clearance of lymphocytic choriomeningitis virus infection

Rode, Miriam; Balkow, Sandra; Sobek, Vera; Brehm, R; Martin, Praxedis; Kersten, A; Dumrese, Tilman; Stehle, Thomas; Mullbacher, Arno; Wallich, Reinhard; Simon, Markus M

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In this report we questioned the current view that the two principal cytotoxic pathways, the exocytosis and the Fas ligand (FasL)/Fas-mediated pathway, have largely nonoverlapping biological roles. For this purpose we have analyzed the response of mice that lack Fas as well as granzyme A (gzmA) and gzmB (FasxgzmAxB-/-) to infection with lymphocytic choriomeningitis virus (LCMV). We show that FasxgzmAxB-/- mice, in contrast to B6, Fas-/-, and gzmAxB-/- mice, do not recover from a primary...[Show more]

dc.contributor.authorRode, Miriam
dc.contributor.authorBalkow, Sandra
dc.contributor.authorSobek, Vera
dc.contributor.authorBrehm, R
dc.contributor.authorMartin, Praxedis
dc.contributor.authorKersten, A
dc.contributor.authorDumrese, Tilman
dc.contributor.authorStehle, Thomas
dc.contributor.authorMullbacher, Arno
dc.contributor.authorWallich, Reinhard
dc.contributor.authorSimon, Markus M
dc.date.accessioned2015-12-13T22:40:23Z
dc.date.available2015-12-13T22:40:23Z
dc.identifier.issn0022-538X
dc.identifier.urihttp://hdl.handle.net/1885/78221
dc.description.abstractIn this report we questioned the current view that the two principal cytotoxic pathways, the exocytosis and the Fas ligand (FasL)/Fas-mediated pathway, have largely nonoverlapping biological roles. For this purpose we have analyzed the response of mice that lack Fas as well as granzyme A (gzmA) and gzmB (FasxgzmAxB-/-) to infection with lymphocytic choriomeningitis virus (LCMV). We show that FasxgzmAxB-/- mice, in contrast to B6, Fas-/-, and gzmAxB-/- mice, do not recover from a primary infection with LCMV, in spite of the expression of comparable numbers of LCMV-immune and gamma interferon-producing cytotoxic T lymphocytes (CTL) in all mouse strains tested. Ex vivo-derived FasxgzmAxB-/- CTL lacked nucleolytic activity and expressed reduced cytolytic activity compared to B6 and Fas-/- CTL. Furthermore, virus-immune CTL with functional FasL and perforin (gzmAxB-/-) are more potent in causing target cell apoptosis in vitro than those expressing FasL alone (perfxgzmAxB-/-). This synergistic effect of perforin on Fas-mediated nucleolysis of target cells is indicated by the fact that, compared to perfxgzmAxB-/- CTL, gzmAxB-/- CTL induced (i) an accelerated decrease in mitochondrial transmembrane potential, (ii) increased generation of reactive oxygen species, and (iii) accelerated phosphatidylserine exposure on plasma membranes. We conclude that perforin does not mediate recovery from LCMV by itself but plays a vital role in both gzmA/B and FasL/Fas-mediated CTL activities, including apoptosis and control of viral infections.
dc.publisherAmerican Society for Microbiology
dc.sourceJournal of Virology
dc.subjectKeywords: Fas antigen; gamma interferon; granzyme A; granzyme B; perforin; phosphatidylserine; reactive oxygen metabolite; animal cell; animal experiment; animal model; animal tissue; apoptosis; article; controlled study; convalescence; cytotoxic lymphocyte; cytoto
dc.titlePerforin and Fas act together in the inductin of apoptosis, and both are critical in the clearance of lymphocytic choriomeningitis virus infection
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume78
dc.date.issued2004
local.identifier.absfor110799 - Immunology not elsewhere classified
local.identifier.ariespublicationMigratedxPub6897
local.type.statusPublished Version
local.contributor.affiliationRode, Miriam, Max Planck Institute of Immunobiology
local.contributor.affiliationBalkow, Sandra, Max Planck Institute of Immunobiology
local.contributor.affiliationSobek, Vera, Max Planck Institute of Immunobiology
local.contributor.affiliationBrehm, R, Max Planck Institute of Immunobiology
local.contributor.affiliationMartin, Praxedis, Max Planck Institute of Immunobiology
local.contributor.affiliationKersten, A, University of Freiberg
local.contributor.affiliationDumrese, Tilman, Institute of Experimental Immunology
local.contributor.affiliationStehle, Thomas, Max Planck Institute of Immunobiology
local.contributor.affiliationMullbacher, Arno, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationWallich, Reinhard, Max Planck Institute of Immunobiology
local.contributor.affiliationSimon, Markus M, Max Planck Institute of Immunobiology
local.bibliographicCitation.issue22
local.bibliographicCitation.startpage12395
local.bibliographicCitation.lastpage12405
local.identifier.doi10.1128/JVI.78.22.12395-12405.2004
dc.date.updated2016-02-24T09:48:59Z
local.identifier.scopusID2-s2.0-7644243776
CollectionsANU Research Publications

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