title: Perforin and Fas act together in the induction of apoptosis, and both are critical in the clearance of lymphocytic choriomeningitis virus infection.
abstract: 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 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.
authors.affiliation: Max-Planck-Institut für Immunbiologie, Stübeweg 51, D-79108 Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rode
authors.forename: Sandra
authors.initials: S
authors.lastname: Balkow
authors.forename: Vera
authors.initials: V
authors.lastname: Sobek
authors.forename: Reina
authors.initials: R
authors.lastname: Brehm
authors.forename: Praxedis
authors.initials: P
authors.lastname: Martin
authors.forename: Astrid
authors.initials: A
authors.lastname: Kersten
authors.forename: Tilman
authors.initials: T
authors.lastname: Dumrese
authors.forename: Thomas
authors.initials: T
authors.lastname: Stehle
authors.forename: Arno
authors.initials: A
authors.lastname: Müllbacher
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D017209:Apoptosis; D010450:Endopeptidases / Q000502:physiology; D053222:Fas Ligand Protein; D053804:Granzymes; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D012697:Serine Endopeptidases / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D000943:Antigens, Differentiation; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D017382:Reactive Oxygen Species; D019014:fas Receptor; D054353:Perforin; D010450:Endopeptidases; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases