抗 原 加 工 提 呈Antigen Processing and Presentation PPT课件

抗原加工提呈（AntigenProcessingandPresentation）张勇TcellsdonotrecognizenativeantigensAntigensmustbeprocessedinordertoberecognizedbyTcellsTcellresponseNoTcellresponseNoTcellresponseNoTcellresponseNoTcellresponseAgprocessingandpresentationSinceallcellsexpressingeitherclassIorclassIIMHCmoleculescanpresentpeptidestoTcells,strictlyspeakingtheyallcouldbedesignatedasAntigenPresentingCells(APC).However,………………..Targetcells:CellsthatdisplaypeptidesassociatedwithclassIMHCmoleculestoCD8+Tccellsarereferredtoastargetcells.Professionalantigenpresentingcells(APC):CellsthatdisplaypeptidesassociatedwithclassIIMHCmoleculestoCD4+ThcellsarecalledAPC.APCs:highlyspecializedcellsUptakeandprocessantigensExpressco-stimulatorymolecules(B7)ExpressclassIIMHCmoleculesPresentantigenicpeptidetoCD4+T-cellthemainAPCsare:dendriticcells,macrophagesandBcells.The3typesofAPCsConstitutivelyexpressahighlevelofMHCIIandtheco-stimulatoryprotein,B7.themosteffectiveAPCConstitutivelyexpressclassIIMHCbutmustbeactivatedtoproduceB7.mustbeactivatedbytheprocessofphagocytosisbeforeexpressingclassIIMHCandB7.1.dendriticcell(DC)discoveredin1973Tissue–residentDCsurfacereceptorsrecognizemicrobesImmatureDC(iDC)migratetolocallymphnodesWithinlymphnodesDCpresentantigenstoTcellsinMHCmoleculesmatureDC(mDC)iDCmDCLowlevelsofclassIIMHCandB7StronglyinternalizeantigensbuthavenopresentationabilityhighlevelsofclassIIMHCandB7Stronglypresentantigensbutcan’tuptakeantigensmonocyte：bloodmacrophage：tissue2.macrophage(M) receptors mannosereceptor LPSreceptor CRandFcRspecializedtointernalizeparticleantigensMHCandco-stimulatorymoleculesclassⅡMHC：inducibleexpressedafterphagocytosisB7：inducibleexpressedafterphagocytosis BCR(smIg):takeupsolubleantigensefficintly ConstitutivelyexpressclassⅡMHC InducibleexpressionofB73.BlymphocyteThepropertiesofvariousAPCsantigenprocessingproteinantigenisdegradedintopeptideantigenpresentationassociationofpeptidewithMHCandtransportationofMHC-peptidecomplextothecellmembraneAntigenprocessingandpresentationendogenousantigens：proteinsthataresynthesizedwithinthecytoplasmofthecell.Examples:viralproteins,tumorantigensexogenousantigens：antigensoriginateoutsidethecell.Examples:bacteriaproteinsProcessingandPresentationofEndogenousAntigens(MHCclassIpathway)DegradationintheproteasomeThecomponentsoftheproteasomeincludeMECL-1,LMP2,LMP7LMP2&7encodedintheMHCProteasomecleavesproteinsafterhydrophobicandreleasespeptidesintothecytoplasmCytoplasmiccellularproteins,includingnon-selfproteinsaredegradedcontinuouslybyamulticatalyticproteaseof28subunitsENDOPLASMICRETICULUMCYTOSOLPeptideantigensproducedinthecytoplasmarephysicallyseparatedfromnewlyformedMHCclassITransportersassociatedwithantigenprocessing(TAP1&2)Transporterhaspreferencefor>8aminoacidpeptideswithhydrophobicCtermini.CalnexinbindstonascentclassIchainuntil2-mbindsB2-mbindsandstabilisesfloppyMHCTapasin,calreticulin,TAP1&2formacomplexwiththefloppyMHCCytoplasmicpeptidesareloadedontotheMHCmoleculeandthestructurebecomescompactMaturationandloadingofMHCclassIFateofMHCclassIThepresentationofClassIMHC/peptidebyatargetcelltoaCD8+TccellresultsintheproliferationandsubsequentdifferentiationofaTcintoakiller/effectorcell.TheTccanthenparticipateinTARGETCELLKILLING.Targetcell“kissofdead”ProcessingandPresentationofExogenousAntigens(MHCclassIIpathway)YPinocytosisPhagocytosisMembraneIgreceptormediateduptakeUptakeofexogenousantigensComplementreceptormediatedphagocytosisFcreceptormediatedphagocytosisUptakemechanismsdirectantigenintointracellularvesiclesforexogenousantigenprocessingProteasesproduce15~30aminoacidslongpeptidesfromantigensExogenouspathwayProteinantigensInendosomeCathepsinB,DandLproteasesareactivatedbythedecreaseinpHNeedtopreventnewlysynthesised,unfoldedselfproteinsfrombindingtoimmatureMHCInvariantchainstabilisesMHCclassIIbynon-covalentlybindingtotheimmatureMHCclassIImoleculeandforminganonomericcomplexIntheendoplasmicreticulumMHCclassIImaturationandinvariantchainClassIIassociatedinvariantchainpeptide(CLIP)(Ii)3complexesdirectedtowardsendosomesbyinvariantchainCathepsinLdegradesInvariantchainCLIPblocksgrooveinMHCmoleculeMHCClassIIcontainingvesiclesfusewithantigencontainingvesiclesRemovalofCLIP?Howcanthepeptidestablybindtoafloppybindingsite?CompetitionbetweenlargenumberofpeptidesHLA-DMcatalysestheremovalofCLIPMIICcompartmentHLA-DMReplacesCLIPwithapeptideantigenusingacatalyticmechanismMIICcompartmentsortspeptide-MHCcomplexesforsurfaceexpressionorlysosomaldegradationSurfaceexpressionofMHCclassII-peptidecomplexesTheresultofClassIIMHC/peptidebyanAPCtoaCD4+Thcellis:ACTIVATIONandPROLIFERATIONoftheThcellandthen“help”otherimmuno-cellstoactivate.Separateantigen-presentingpathwaysareutilizedforendogenous(green)andexogenous(red)antigens.ThemodeofantigenentryintocellsandthesiteofantigenprocessingdeterminewhetherantigenicpeptidesassociatewithclassIMHCmoleculesintheroughendoplasmicreticulumorwithclassIImoleculesinendocyticcompartments.内源性和外源性抗原加工途径特点比较 特点 内源性抗原加工途径 外源性抗原加工途径 提呈抗原肽的MHC分子 I类分子 II类分子 应答的T细胞 CD8+T细胞 CD4+T细胞 抗原来源 内源性 外源性 抗原肽产生部位 胞内蛋白酶体 内体、溶酶体 MHC荷肽部位 内质网腔 CIIV或MIIC 伴随蛋白 钙联素，TAP，tapasin 钙联素，Ii链 提呈细胞 所有有核细胞 专职APC本章要求：1.掌握APC的概念、种类及生物学功能。2.掌握内源性和外源性抗原加工提呈的过程。3.掌握下列常用名词：抗原加工提呈、APC、内源性抗原、外源性抗原