医学免疫学-抗原递呈细胞和抗原递呈

抗原递呈细胞和抗原递呈Antigen-presentingCells(APC)andAntigenPresentation

免疫学系122232KillActivatemacrophagesProduceAbs42TCellFunctionsCD8+CytotoxicTcells,CTLEliminatevirus-infectedcellsCD4+HelperTcells,ThActivatemacrophagesandBcells52CytotoxicTcell(CTL,CD8+)

Directlykillvirus-infectedcell62HelperTcells(Th,CD4+)

ActivateMacrophagesandBcells72抗原递呈效应性T细胞产生效应CD4+Th

vsCD8+CTL？初始化的T细胞活化82ChallengesforTcellstoovercomeAg-specificTcellsarerare.Infectionmayoccuratanysiteinthebody.Antigen-presentingcells(APC)capture,presentantigenandactivateTcells.92102ChallengesforTcellstoovercomeAg-specificTcellsarerare.Infectionmayoccuratanysiteinthebody.Antigen-presentingcells(APC)capture,presentantigenandactivateTcells.112122132抗原递呈效应性T细胞产生效应初始化的T细胞活化142HowdoTcellsrecognizeAg?152TheT-cellreceptorresemblesamembrane-associatedFabfragmentofimmunoglobulin162172B-cellreceptorsorantibodiesrecognizepeptides,proteins,nucleicacids,carbohydrates,lipidsandsmallchemicals.T-cellreceptorsrecognizeonlyshortlinearpeptides.182192EveryTCRisspecificforacombinationofapeptideAgandpartsofMHC(MHCrestriction).202MHCIandMHCII212MHCI,allnucleatedcellsMHCII,APC222MHCcellsurfaceexpressionAllnucleatedcellsexpressMHCClassI,presentingAgtoCD8+Tcells.Antigen-presentingcells(DC,Mac,B)displayAginMHCClassIItoCD4+Tcells.232Peptide-MHCICD8TcellPeptide-MHCIICD4Tcell242Antigen-presentingCells(APC)252APCs:

SpecializedcellsthatpresentAgstoCD4+Tcells262ActivatenaïveoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells272ActivatenaïveoreffectorCD4+Tcells.ExpressMHCIIDCnaïveTcellsMac,BactivatedTAg-presentingCells282ActivatenaïveoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells292NaïveTcellactivationrequires2signalsSignal1=MHC-AgTCRSignal2=CostimulatorsB7(CD80/86)CD28CD40CD40LSignal3=Cytokines,IL-12302NaïveTcellactivationrequires2signals312ImmuneSynapse322ActivatenaïveoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells332InnateRecognition(PAMPandPRR)Conserved,essential,characteristicmolecules,absentinthehostPRRPAMP342352PAMPEnhancesAntigen-presentingfunctionsofAPCsAPCsexpressTLRsandotherPRRs.Signal1=MHC-peptideTCRSignal2=CostimulatorsSignal3=Cytokines362Adjuvant(microbialproductsorderivatives)

Immunologist’sdirtylittlesecret372ActivatenaïveoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells382CD40(APC)-CD40L(T)IFN-γPositivefeedbacktomaximizetheimmuneresponses392DendriticCells402Ralph.M.Steinman,RockfellerUniversitySteinmanRM,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.1973,JExpMed.DendriticCells412TheNobelPrizeinPhysiologyorMedicine2011BruceBeutlerRalphSteinmanJulesHoffmann422ConventionalDCPlasmacytoidDCDendriticcells432442Naturalreviewsimmunology,2014452EpithelialLangerhansCellTheLangerhanscellisnamedafterPaulLangerhans,aGermanphysicianandanatomist,whodiscoveredthecellsattheageof21whilehewasamedicalstudent.Becauseoftheirdendriticnature,hemistakenlyidentifiedthecellsaspartofthenervoussystem.462DCinthegut472ThemosteffectiveAPCsforactivatingnaïveTcells.Dedicated(professional)APC.DCsformthebridgebetweeninnateandadaptiveimmuneresponses.DendriticCells482Immaturevs.MatureDCsImmatureDC(AgCapture)MatureDC(AgPresentation)492ImmatureDCslocalizeatskinormucosalsurfaces502DCMaturation512

未成熟DC成熟DC主要功能抗原的摄取、加工抗原递呈C-型凝集素受体、甘露糖受体、Fc受体的表达+++/-抗原摄取及加工功能+++/-趋化因子CCR7受体表达+/-++MHCII类分子表达+/-++共刺激分子表达+/-++粘附分子表达+/-++细胞因子（IL-12）分泌+/-++抗原递呈能力+/-++未成熟和成熟DC特点的比较522532542AntigenpresentationandTcellactivation552LymphNodeConduitSystem562LymphNodeConduitSystem572DCsInterdigitateBetweenTheReticularCells582OtherLymphoidOrgansPeyer’spatchesGastrointestinalmucosalsurfaceTonsilsUpperrespiratorysystemsSpleenBlood592602ImmatureDCslocatestrategicallyatepitheliaormucosalsurfaceCaptureandrespondtomicrobesMigratetoLNTcellzoneMatureandexpresshighMHC,co-stimulatorymoleculesandcytokinesVerypotentatactivatingnaïveTcellsDendriticCell,themostefficientAPC612Antigen-presentingcells622MacpresenttheAgsofphagocytosedmicrobestoeffectorTcells,whichrespondbyactivatingMactokillthemicrobes.632642BcellscanusetheirsurfaceIgtopresentspecificAgveryefficientlytoTcells.652HelperTcells(Th,CD4+)

ActivateMacrophagesandBcells662

DC巨噬细胞B细胞递呈对象初始化T细胞效应性CD4+Th细胞效应性CD4+Th细胞抗原摄取吞噬作用、胞饮作用（未成熟DC）吞噬作用、胞饮作用BCR介导的内吞作用胞饮作用MHCII表达未成熟DC低成熟DC高PAMP和细胞因子诱导持续表达，活化后进一步升高共刺激分子表达未成熟DC低成熟DC高PAMP和细胞因子诱导活化诱导位置全身淋巴组织、结缔组织、体腔淋巴组织、外周血主要功能启动适应性免疫反应初始化T细胞活化增殖并分化为效应性T细胞增强巨噬细胞活性(细胞免疫)B细胞活化分化，产生抗体（体液免疫）专职性抗原递呈细胞特性和功能的比较672682CytotoxicTcell(CTL,CD8+)

Directlykillvirus-infectedcell692SummaryTcellfunctions(CTLandTh)NaiveTcellactivationTCRrecognizespeptideAgpresentedbyMHCAg-MHCICD8T;Ag-MHCIICD4TAPCCD4Tcells;2ndsignal;adjuvant-activation;bidirectionalinteractionwithTcell.DC,themostpotentAPCandDCmaturationAntigenpresentationbymacrophagesandBcells702712抗原递呈的意义为什么要有两种途径的抗原递呈？722732Antigenprocessingandpresentation742Antigenprocessingandpresentation752762ProteinAgsincytosolpeptide-MHCICD8TcellsAgsinternalizedfromextracellularenvironment(Vesicular)peptide-MHCIICD4TcellsCross-presentationAntigenpresentationpathways772ProteinAgsincytosolpeptide-MHCICD8TcellsAgsinternalizedfromextracellularenvironment(Vesicular)peptide-MHCIICD4TcellsCross-presentationAntigenpresentationpathways782CytosolicProteins,MHCClassIPathway792SourcesofCytosolicProteinAgsVirusorintracellularmicrobesTumorAgsPhagosomeCytosolMisfoldedproteins--ER-associateddegradation802ER-associatedDegradation812Proteasome822Immuno-proteasomeIFN-γProducepeptideswithhydrophobicorbasicAAatcarboxyl-termini.TheproductsaregoodsubstratesforTAPtransferandClassIloading.832842TAP=TransporterAssociatedwithAntigenProcessingTAP1/TAP2heterodimerATP-dependent8-16AApeptidesBasicorhydrophobiccarboxyltermini852MHCIαchainsandβ-microglobulinaresynthesizedinER.ChaperoneproteinsassistappropriatefoldingofMHCIαchains.Calreticulin，Tapasin，ERp57,TAP(peptide-loadingcomplex)ERAP(ERresidentaminopeptidase)-PeptideeditingPeptide-MHCIistransportedtocellsurfacebyexocyticvesicles.862ERAP(ERresidentaminopeptidase)872HumanMHC882PeptidesgeneratedinthecytosolaretransportedintotheERwheretheybindMHCclassImoleculesIntracellularPathogensProteasome-degradeintracellularproteinsTransporterassociatedwithantigenprocessing(TAP)-transportsproteinsacrossERmembraneChaperoneproteinsmakethingsproceedsmoothlyAfinalprocessing(Trim)occursbeforeshippedofftothemembraneInsertedonmembranesurfacewithpeptide/MHCclassICD8Tcells892902912ProteinAgsincytosolpeptide-MHCICD8TcellsAgsinternalizedfromextracellularenvironment(Vesicular)peptide-MHCIICD4TcellsCross-presentationAntigenpresentationpathways922Extracellularproteins,MHCClassIIpathway932GenerationofvesicularproteinAgsCapturedfromtheextracellularenvironmentandinternalizedintoendosomesMR,C-typelectinsFc,C3breceptorsBCRPinocytosisPhagocytosis942952Theinvariantchainiscleavedtoleaveapeptidefragment,CLIP,boundtotheMHCclassIImoleculeCLIP(classII-associated

invariant-chainpeptide)962Ii链的功能促进MHCII类分子组装和折叠阻止MHCII类分子在ER内与其他多肽结合促进MHCII类分子的转运972Vesicularproteins,MHCClassIIpathway9829921002HumanMHC1012PeptidespresentedbyMHCclassIImoleculesaregeneratedinacidifiedintracellularvesiclesExtracellularpathogensPhagosomesfusewithlysosomesandformphagolysosomesMHCclassIImoleculesarepreventedfrombindingpeptidesintheERbytheinvariantchainInvariantchainbecomesclassII-associatedinvariantchainpeptide(CLIP)invesicleCLIPisrem