浙江大學醫(yī)學免疫學經(jīng)典課件免疫11-apc

Antigen-PresentingCellsandAntigenPresentationxiaojianWangInstituteofImmunologyZhejiangUniversity

IntroductionAntigen-presentingcellsAntigenprocessingandpresentationContentsI.Antigen-presentingcell,APCAntigen-presentingcellsarerequiredforTcellactivationAPC染色彩圖Antigen-presentingcellsDendriticcellsMacrophagesBcells

Non-professionalAPCEndothelialcell(EC)FibroblasticcellActivatedTcellUndersomecircumstances,theycanexpressMHCIIandpresentAgsII.Antigenpresentation

TheprocessbywhichAPCexpresspeptide-MHContheircellsurfaceinaformrecognizablebylymphocytes.I.DendriticcellshighlybranchedmorphologycanactivenaiveTcellsmarkersTheNobelPrizeinPhysiologyorMedicine2011拉爾夫·斯坦曼（RalphM.Steinman）【已故】1943年出生于加拿大蒙特利爾，在麥吉爾大學學習生物學和化學。之后在美國哈佛醫(yī)學院學習醫(yī)學，1968年獲得醫(yī)學博士學位（MD）。于1970年被紐約洛克菲勒大學接納，從1988年起成為免疫學教授。擔任該校免疫學與免疫性疾病中心主任。

發(fā)現(xiàn)樹突狀細胞Dendriticcells,DC是啟動適應性免疫應答的關鍵細胞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