Protection of Hepatocytes from Cytotoxic T Cell Mediated Killing by Interferon-Alpha 英文参考文献.docVIP

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Protection of Hepatocytes from Cytotoxic T Cell Mediated Killing by Interferon-Alpha 英文参考文献.doc

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Protection of Hepatocytes from Cytotoxic T Cell Mediated Killing by Interferon-Alpha 英文参考文献

ProtectionofHepatocytesfromCytotoxicTCell MediatedKillingbyInterferon-Alpha ChristianB.Willberg1,5,ScottM.Ward1,6,ReginaldF.Clayton2,NikolaiV.Naoumov3,ChristopherMcCormick4,7,SandraProto3,MarkHarris4, ArvindH.Patel2,PaulKlenerman1* 1NuffieldDepartmentofMedicine,OxfordUniversity,Oxford,UnitedKingdom,2MedicalResearchCouncilVirologyUnit,Glasgow,UnitedKingdom, 3The University College London Institute of Hepatology, University College London, London, United Kingdom, 4Faculty of Biological Sciences, InstituteofMolecularandCellularBiology,UniversityofLeeds,Leeds,UnitedKingdom,5DivisionofExperimentalMedicine,UniversityofCaliforniaat SanFrancisco,SanFrancisco,California,UnitedStatesofAmerica,6PrincessAlexandraHospital,Woolloongabba,Australia,7MolecularMicrobiology andInfection,UniversityofSouthampton,SouthamptonGeneralHospital,Southampton,UnitedKingdom Background.CellularimmunityplaysakeyroleindeterminingtheoutcomeofhepatitisCvirus(HCV)infection,althoughthe majorityofinfectionsbecomepersistent.Themechanismsbehindpersistencearestillnotclear;however,theprimarysiteof infection,theliver,maybecritical.WeinvestigatedtheabilityofCD8+T-cells(CTL)torecogniseandkillhepatocytesunder cytokinestimulation. Methods/Principle Findings.Resting hepatocytes celllinesexpressedlowlevels ofMHCClassI,but remained susceptible to CTL cytotoxicity. IFN-a treatment, in vitro, markedly increased hepatocyte MHC Class I expression, however, reduced sensitivity to CTL cytotoxicity. IFN-a stimulated hepatocyte lines were still able to present antigen and induceIFN-cexpressionininteractingCTL.ResistancetokillingwasnotduetotheinhibitionoftheFASL/FAS-pathway,as stimulatedhepatocyteswerestillsusceptibletoFAS-mediatedapoptosis.InvitrostimulationwithIFN-a,ortheintroductionof asubgenomicHCVrepliconintotheHepG2line,upregulatedtheexpressionofthegranzyme-Binhibitor–proteinaseinhibitor 9 (PI-9). PI-9 expression was also observed in liver tissue biopsies from patients with chronic HCV infection. Conclusion/ Signif