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Antigen-PresentingCellsandAntigenPresentationxiaojianWangInstituteofImmunologyZhejiangUniversity
IntroductionAntigen-presentingcellsAntigenprocessingandpresentationContentsI.Antigen-presentingcell,APCAntigen-presentingcellsarerequiredforTcellactivationAPC染色彩图Antigen-presentingcellsDendriticcellsMacrophagesBcells
Non-professionalAPCEndothelialcell(EC)FibroblasticcellActivatedTcellUndersomecircumstances,theycanexpressMHCIIandpresentAgsII.Antigenpresentation
TheprocessbywhichAPCexpresspeptide-MHContheircellsurfaceinaformrecognizablebylymphocytes.I.DendriticcellshighlybranchedmorphologycanactivenaiveTcellsmarkersTheNobelPrizeinPhysiologyorMedicine2011拉尔夫·斯坦曼（RalphM.Steinman）【已故】1943年出生于加拿大蒙特利尔，在麦吉尔大学学习生物学和化学。之后在美国哈佛医学院学习医学，1968年获得医学博士学位（MD）。于1970年被纽约洛克菲勒大学接纳，从1988年起成为免疫学教授。担任该校免疫学与免疫性疾病中心主任。
发现树突状细胞Dendriticcells,DC是启动适应性免疫应答的关键细胞R.M.SteinmanandZ.A.Cohn.J.Exp.Med.137,1142–1162;1973
1.SurfacemarkersMHCclassI/IImoleculesCD1a,CD11c,CD83(human)33D1,NLDC145(mouse)Co-stimulatorymolecules:B7.1(CD80)/B7.2(CD86),CD40,CD44,CD543.DistributionandClassificationofDCDCsarefoundinmanyorgansthroughoutthebodyDCinlymphoidtissue-LymphoidtissueDCInterdigitatingcell,IDCFollicularDC,FDCthymicdendriticcell,TDCDCnotinlymphoidtissue-Non-lymphoidtissueDCLangerhanscellsInterstitialDCDCinbodyfluid-CirculatingDCVeiledcellsPeripheralbloodDCLocatedinlymphfollicleswhicharerichinBcells;DerivedfrominterstitialDC;HighlyexpressFcR,CR1andCR2;InvolvedinthegenerationandmaintenanceofmemoryBcells.1)FollicularDC(FDC)FollicularDC,FDCBcellsFDCFDCexpresshighlevelsofmembranereceptorsforantibodyandcomplement.Bythese,FDCactivestheBcellsinlymphnodes.3)Langerhanscells(LC)Foundintheepidermis(skin)andmucousmembranes;MHCIandIIhigh,highlyexpressFcRandC3bR,Birbeckparticle(duetolangerinexpression);PowerfulabilitytocaptureandprocessAgsandmigrationtolymphnodeafteractivation.LangerhansIDC4.DevelopmentofmyeloidDCFourphasesPre-DCMonocyte,MoImmatureDCUptakeantigenMigrationMatureDCExpresshighlevelsofMHCIandII,CD80,CD86,CD40,CD54,HSP,etc.ImmatureDC
Phenotype:highexpressionofreceptorsrelatedtophagocytosis(FcR,CR,mannosereceptor,DC-sign);lowexpressionofCD54,CD40,CD80;CD86andMHCII,CD14-Function:1)strongcapacitytoingestandprocessAgs,butweakabilitytopresentAgs2)inductionofimmunetolerance3)sensingofinfectiousagentsbyTLR(patternrecognitionreceptors)
DendriticCellMaturationMHCII5.DCinimmuneactivationandimmunetolerance1)DCinimmuneactivation
PresentantigenandactivateTcells①ThefirstsignalMHCII-Ag:CD4+TcellsMHCI-Ag:CD8+Tcells②Thesecondsignalco-stimulatingmoleculescytokinesIL-12
BonemarrowBloodTissueHSCMyeloidprogenitorPre-monocyteMonocyteMonocyteMacrophageIIMononuclearphagocytesystem(MPS)
1.DifferentiationanddistributionDifferentnamesindifferenttissuesMonocyte(blood)Kupffercells(liver)Mesangialcells(kidneyglomerulus)Microglia(brain)Alveolarmacrophages(lung)Histiocyte(connectivetissue)
Antimicrobialandcytotoxicactivity:anumberofantimicrobialandcytotoxicsubstancesproducedbyactivatedMcandestroyphagocytosedmicroorganisms.
Reactiveoxygenintermediates,nitricoxide.
Secretionofsolublefactors:
enzymes:lysozyme,myeloperoxidase,etc.cytokines:IL-1,IL-6,TNF,IL-12,IL-18,plement:C1~C9,Bfcoagulationfactors,PG,LTs,ACTH,etc.phagocytosismacrophageAgpresentation
III.Bcells
bonemarrow-dependentlymphocyteAbout5-15%ofthecirculatinglymphoidpoolareBcellsdefinedbythepresenceofsurfaceimmunoglobulin(Ig).III.BcellsAntigenprocessingandpresentationBindinganduptakeofantigendependsonthephysicalstateoftheantigenandthecelltypeinvolved.AntigenprocessingMHCclassIprocessingpathwayMHCclassIIprocessingpathwayAntigenpresentation1BindinganduptakeofantigenEndogenousantigens:MHCI-CD8Producedwithinthecells,SuchasviralproteinsortumorproteinsprocessedbyhostcellExogenousantigens:MHCII-CD4Producedoutofthecells,Bacteria,cellsandsolubleproteinsprocessedbyAPCUptakeantigenbyimmatureDCandmacrophage
PinocytosisLiquidorsmallgranulePhagocytosisLargemolecularormicrobeReceptor-mediatedendocytosiseffectiveSelectivenonspecificallyengulfedBCR-mediatedUptakeantigenbyBcells2
AntigenprocessingDegradationofexternally-orinternally-derivedantigenintoshortpeptidesequencesAssociationofthepeptidewithMHCmolecules1.ThepathwayofMHCI-associatedendogenousAgpresentationtransportedtoendoplasmicreticulumbyTAPdegradedbyproteasome(LMP2/7)incytoplasm
endogenousantigen(suchasvirusAg,tumorAg)
antigenpeptide（8-10aa）
Peptide/MHC-Imoleculecomplex
tosurfaceofAPC
presenttoCD8+T
killtheinfectedormutatedcellsDegradationintheproteasomeThecomponentsoftheproteasomeincludeMECL-1,LMP2,LMP7.Proteinincellsincludingnon-selfproteinsaredegradedcontinuouslybyamulticatalyticproteaseof28subunitsProteasome,theCytosolicMeatGrinderThatChopsUpProteinsENDOPLASMICRETICULUMCYTOSOLPeptideantigensproducedinthecytoplasmarephysicallyseparatedfromnewlyformedMHCclassINewlysynthesisedMHCclassImoleculesPeptidesneedaccesstotheERinordertobeloadedontoMHCclassImoleculesLMPTAPERmembraneLumenofERCytosolTransporter-associatedwithantigenprocessing(TAP1&2)Transporterhaspreferencefor>8aminoacidpeptideswithhydrophobicCtermini.TAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideERmembraneLumenofERCytosolTAP-1TAP-2PeptideATP-bindingcassette(ABC)domainHydrophobictransmembranedomainPeptideantigensfromproteasomeEndoplasmicreticulumCalnexinbindstonascentclassIchainuntil2-MbindsTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2Peptide2-MbindsandstabilisesfloppyMHCTapasin,calreticulin,TAP1&2formacomplexwiththefloppyMHCCytoplasmicpeptidesareloadedontotheMHCmoleculeandthestructurebecomescompactMaturationandloadingofMHCclassI2.ThepathwayofMHCII-associatedexogenousAgpresentationExogenousantigennewlysynthesisedMHCclassIImolecule
(intheendoplasmicreticulum)endosomeIibindsinthegrooveofMHCclassIImolecule
lysosomeproteaseMIICphagolysosomeliCLIPproteaseDMDegradeinto1215aapeptide+releasingtheCLIPandallowingotherpeptidetobind
Agpeptide/MHCclassIImoleculecomplextransporttothesurfaceofAPC,recognizedbyCD4+TPhagocytosis,pinocytosis,FcR-phagocytosisBCR-receptorYYPinocytosisPhagocytosisMembraneIgreceptormediateduptakeYUptakeofexogenousantigensComplementreceptormediatedphagocytosisYFcreceptormediatedphagocytosisopsonizationProteasesproduce~24aminoacidlongpeptidesfromantigensEndosomesExogenouspathwayIncreaseinacidityCellsurfaceTolysosomesUptakeProteinantigensInendosomeCathepsinB,DandLproteasesareactivatedbythedecreaseinpHNeedtopreventnewlysynthesised,unfoldedselfproteinsfrombindingtoimmatureMHCInvariantchainstabilisesMHCclassIIbynon-covalentlybindingtotheimmatureMHCclassIImoleculeandforminganonomericcomplexIntheendoplasmicreticulumMHCclassIImaturationandinvariantchaininvolveintheassemblingandfoldingofMHCclassIImolecule;BlockthegrooveofMHCclassIImolecule;LeadtheassembledclassIImoleculetoMIIC.ThefunctionsofIi:CLIP：classII-associatedinvariantchainpeptideHLA-DMcatalysestheremovalofCLIPMIICcompartmentHLA-DMReplacesCLIPwithapeptideantigenusingacatalyticmechanism(i.e.efficientatsub-stoichiometriclevels)DiscoveredusingmutantcelllinesthatfailedtopresentantigenHLA-DOmayalsoplayaroleinpeptideexchangeSequenceincytoplasmictailretainsHLA-DMinendosomesHLA-DMHLA-DRMIICcompartmentsortspeptide-MHCcomplexesforsurfaceexpressionorlysosomaldegradationSurfaceexpressionofMHCclassII-peptidecomplexesExportedtothecellsurfaceSenttolysosomesfordegradationImportantaspectsofAgprocessingLocationofp
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