醫(yī)學免疫學-抗原遞呈細胞和抗原遞呈

抗原遞呈細胞和抗原遞呈Antigen-presentingCells(APC)andAntigenPresentation

免疫學系122232KillActivatemacrophagesProduceAbs42TCellFunctionsCD8+CytotoxicTcells,CTLEliminatevirus-infectedcellsCD4+HelperTcells,ThActivatemacrophagesandBcells52CytotoxicTcell(CTL,CD8+)

Directlykillvirus-infectedcell62HelperTcells(Th,CD4+)

ActivateMacrophagesandBcells72抗原遞呈效應性T細胞產(chǎn)生效應CD4+Th

vsCD8+CTL？初始化的T細胞活化82ChallengesforTcellstoovercomeAg-specificTcellsarerare.Infectionmayoccuratanysiteinthebody.Antigen-presentingcells(APC)capture,presentantigenandactivateTcells.92102ChallengesforTcellstoovercomeAg-specificTcellsarerare.Infectionmayoccuratanysiteinthebody.Antigen-presentingcells(APC)capture,presentantigenandactivateTcells.112122132抗原遞呈效應性T細胞產(chǎn)生效應初始化的T細胞活化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+Tcells262Activatena?veoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells272Activatena?veoreffectorCD4+Tcells.ExpressMHCIIDCna?veTcellsMac,BactivatedTAg-presentingCells282Activatena?veoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells292Na?veTcellactivationrequires2signalsSignal1=MHC-AgTCRSignal2=CostimulatorsB7(CD80/86)CD28CD40CD40LSignal3=Cytokines,IL-12302Na?veTcellactivationrequires2signals312ImmuneSynapse322Activatena?veoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells332InnateRecognition(PAMPandPRR)Conserved,essential,characteristicmolecules,absentinthehostPRRPAMP342352PAMPEnhancesAntigen-presentingfunctionsofAPCsAPCsexpressTLRsandotherPRRs.Signal1=MHC-peptideTCRSignal2=CostimulatorsSignal3=Cytokines362Adjuvant(microbialproductsorderivatives)

Immunologist’sdirtylittlesecret372Activatena?veoreffectorTcells.PresentAgtoTcellsandprovidethe2ndsignal.Microbialproductsenhancetheantigen-presentingfunctionofAPCs.BidirectionalinteractionbetweenAPCandTcells.Ag-presentingCells382CD40(APC)-CD40L(T)IFN-γPositivefeedbacktomaximizetheimmuneresponses392DendriticCells402Ralph.M.Steinman,RockfellerUniversitySteinmanRM,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.1973,JExpMed.DendriticCells412TheNobelPrizeinPhysiologyorMedicine2011BruceBeutlerRalphSteinmanJulesHoffmann422ConventionalDCPlasmacytoidDCDendriticcells432442Naturalreviewsimmunology,2014452EpithelialLangerhansCellTheLangerhanscellisnamedafterPaulLangerhans,aGermanphysicianandanatomist,whodiscoveredthecellsattheageof21whilehewasamedicalstudent.Becauseoftheirdendriticnature,hemistakenlyidentifiedthecellsaspartofthenervoussystem.462DCinthegut472ThemosteffectiveAPCsforactivatingna?veTcells.Dedicated(professional)APC.DCsformthebridgebetweeninnateandadaptiveimmuneresponses.DendriticCells482Immaturevs.MatureDCsImmatureDC(AgCapture)MatureDC(AgPresentation)492ImmatureDCslocalizeatskinormucosalsurfaces502DCMaturation512

未成熟DC成熟DC主要功能抗原的攝取、加工抗原遞呈C-型凝集素受體、甘露糖受體、Fc受體的表達+++/-抗原攝取及加工功能+++/-趨化因子CCR7受體表達+/-++MHCII類分子表達+/-++共刺激分子表達+/-++粘附分子表達+/-++細胞因子（IL-12）分泌+/-++抗原遞呈能力+/-++未成熟和成熟DC特點的比較522532542AntigenpresentationandTcellactivation552LymphNodeConduitSystem562LymphNodeConduitSystem572DCsInterdigitateBetweenTheReticularCells582OtherLymphoidOrgansPeyer’spatchesGastrointestinalmucosalsurfaceTonsilsUpperrespiratorysystemsSpleenBlood592602ImmatureDCslocatestrategicallyatepitheliaormucosalsurfaceCaptureandrespondtomicrobesMigratetoLNTcellzoneMatureandexpresshighMHC,co-stimulatorymoleculesandcytokinesVerypotentatactivatingna?veTcellsDendriticCell,themostefficientAPC612Antigen-presentingcells622MacpresenttheAgsofphagocytosedmicrobestoeffectorTcells,whichrespondbyactivatingMactokillthemicrobes.632642BcellscanusetheirsurfaceIgtopresentspecificAgveryefficientlytoTcells.652HelperTcells(Th,CD4+)

ActivateMacrophagesandBcells662

DC巨噬細胞B細胞遞呈對象初始化T細胞效應性CD4+Th細胞效應性CD4+Th細胞抗原攝取吞噬作用、胞飲作用（未成熟DC）吞噬作用、胞飲作用BCR介導的內(nèi)吞作用胞飲作用MHCII表達未成熟DC低成熟DC高PAMP和細胞因子誘導持續(xù)表達，活化后進一步升高共刺激分子表達未成熟DC低成熟DC高PAMP和細胞因子誘導活化誘導位置全身淋巴組織、結締組織、體腔淋巴組織、外周血主要功能啟動適應性免疫反應初始化T細胞活化增殖并分化為效應性T細胞增強巨噬細胞活性(細胞免疫)B細胞活化分化，產(chǎn)生抗體（體液免疫）專職性抗原遞呈細胞特性和功能的比較672682CytotoxicTcell(CTL,CD8+)

Directlykillvirus-infectedcell692SummaryTcellfunctions(CTLandTh)NaiveTcellactivationTCRrecognizespeptideAgpresentedbyMHCAg-MHCICD8T;Ag-MHCIICD4TAPCCD4Tcells;2ndsignal;adjuvant-activation;bidirectionalinteractionwithTcell.DC,themostpotentAPCandDCmaturationAntigenpresentationbymacrophagesandBcells702712抗原遞呈的意義為什么要有兩種途徑的抗原遞呈？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鏈的功能促進MHCII類分子組裝和折疊阻止MHCII類分子在ER內(nèi)與其他多肽結合促進MHCII類分子的轉運972Vesicularproteins,MHCClassIIpathway9829921002HumanMHC1012PeptidespresentedbyMHCclassIImoleculesaregeneratedinacidifiedintracellularvesiclesExtracellularpathogensPhagosomesfusewithlysosomesandformphagolysosomesMHCclassIImoleculesarepreventedfrombindingpeptidesintheERbytheinvariantchainInvariantchainbecomesclassII-associatedinvariantchainpeptide(CLIP)invesicleCLIPisrem