Hepatitis C virus‐cross‐reactive TCR gene‐modified T cells: a model for immunotherapy against diseases with genomic instability

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: peptide‐;    MHC;    computational modeling;    altered peptide ligands;   

DOI  :  10.1189/jlb.2A1215-561R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Amajorobstaclehinderingthedevelopmentofeffectiveimmunityagainstviralinfections,theirassociateddisease,andcertaincancersistheirinherentgenomicinstability.AccumulationofmutationscanalterprocessingandpresentationofantigensrecognizedbyantibodiesandTcellsthatcanleadtoimmuneescapevariants.Useofanagentthatcanintrinsicallycombatrapidlymutatingviralorcancer‐associatedantigenswouldbequiteadvantageousindevelopingeffectiveimmunityagainstsuchdisease.WeproposethatTcellsharboringcross‐reactiveTCRscouldserveasatherapeuticagentintheseinstances.WiththeuseofhepatitisCvirus,knownforitsgenomicinstabilityasamodelformutatedantigenrecognition,wedemonstratecross‐reactivityagainstimmunogenicandmutagenicnonstructuralprotein3:1406‐1415andnonstructuralprotein3:1073‐1081epitopesinPBL‐derived,TCR‐gene‐modifiedTcells.ThesesingleTCR‐engineeredTcellscanCD8‐independentlyrecognizenaturallyoccurringandepidemiologicallyrelevantmutantvariants.TCR‐peptideMHCmodelingdataallowustorationalizehowTCRstructuralpropertiesaccommodaterecognitionofcertainmutatedepitopesandhowthesesubstitutionsimpacttherequirementofCD8affinityenhancementforrecognition.AbetterunderstandingofsuchTCRs’promiscuousbehaviormayallowforexploitationofthesepropertiestodevelopnovel,adoptiveTcell‐basedtherapiesforviralinfectionsandcancersexhibitingsimilargenomicinstability...

【 授权许可】

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