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1、Antigen-PresentingCellsAntigen-PresentingCellsandandAntigenPresentationAntigenPresentationxiaojianWangInstituteofImmunologyZhejiangUniversity浙江大学医学免疫学免疫11a nIntroductionnAntigen-presentingcellsnAntigenprocessingandpresentationContentsContents浙江大学医学免疫学免疫11aI.Antigen-presentingcell,APCI.Antigen-presen
2、tingcell,APCAntigen-presentingcellsarerequiredforTcellactivationAntigen-presentingcellsarerequiredforTcellactivation浙江大学医学免疫学免疫11anAvarietyofcellsspecializedincapturing、processingandpresenttheantigentotheTlymphocytes,causingeithertoleranceorimmunity.nThesecellsarenameasAnitgenpresentingcell,APCnDend
3、riticcells,monocytes/macrophagesandBcellsareprofessionalAPCs.I.Antigen-presentingcell,APCI.Antigen-presentingcell,APC浙江大学医学免疫学免疫11aAPC染色彩图Antigen-presentingcellsAntigen-presentingcellsDendriticcellsDendriticcellsMacrophagesMacrophagesBcellsBcells浙江大学医学免疫学免疫11a Non-professionalAPCNon-professionalAPCn
4、Endothelialcell(EC)nFibroblasticcellnActivatedTcellUndersomeUndersomecircumstances,theycircumstances,theycanexpressMHCIIcanexpressMHCIIandpresentAgsandpresentAgs浙江大学医学免疫学免疫11aII.AntigenpresentationII.AntigenpresentationTheprocessbywhichAPCexpresspeptide-MHC on their cell surface in a formrecognizabl
5、ebylymphocytes.浙江大学医学免疫学免疫11aAntigen-presentingcellsAntigen-presentingcells浙江大学医学免疫学免疫11aI.DendriticcellsI.DendriticcellsnhighlybranchedmorphologyncanactivenaiveTcellsnmarkers浙江大学医学免疫学免疫11aTheNobelPrizeinPhysiologyorMedicine2011拉尔夫拉尔夫斯坦曼（斯坦曼（RalphM.SteinmanRalphM.Steinman）【已故已故】19431943年出生于加拿大蒙特利尔，在
6、麦吉尔大学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，学习生物学和化学。之后在美国哈佛医学院学习医学，19681968年获得医学博士学位（年获得医学博士学位（MDMD）。）。于于19701970年被纽约洛克菲勒大学接纳，从年被纽约洛克菲勒大学接纳，从19881988年起成为免疫学教授。担任该校免疫学与免疫性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。疾病中心主任。发现树突状细胞发现树突状细胞Dendriticcells,DCDendriticcells,DC是启动适应性免疫应答是启动适应性免疫应答的关键细胞的关键细胞R. M. Steinma
7、n and Z. A. Cohn.J. Exp. Med. 137, 11421162; 1973 浙江大学医学免疫学免疫11a1.Surfacemarkers1.SurfacemarkersnMHCclassI/IImoleculesnCD1a,CD11c,CD83(human)n33D1,NLDC145(mouse)nCo-stimulatorymolecules:B7.1(CD80)/B7.2(CD86),CD40,CD44,CD54浙江大学医学免疫学免疫11a2.SourcesofDC2.SourcesofDCGM-CSFTNF-IL-4HSCMyeloid progenitorLym
8、phoid progenitorMyeloid DC MomacrophageMyeloid DCPMNLymphoid DC浙江大学医学免疫学免疫11a3.3.DistributionandClassificationofDCDistributionandClassificationofDCDCsarefoundinmanyorgansthroughoutthebodyDCsarefoundinmanyorgansthroughoutthebodynDCinlymphoidtissue-DCinlymphoidtissue-LymphoidtissueDCLymphoidtissueDCnI
9、nterdigitatingcell,IDCInterdigitatingcell,IDCnFollicularDC,FDCFollicularDC,FDCnthymicdendriticcell,TDCthymicdendriticcell,TDCnDCnotinlymphoidtissue-DCnotinlymphoidtissue-Non-lymphoidtissueDCNon-lymphoidtissueDCnLangerhanscellsLangerhanscellsnInterstitialDCInterstitialDCnDCinbodyfluid-DCinbodyfluid-C
10、irculatingDCCirculatingDCnVeiledcellsVeiledcellsnPeripheralbloodDCPeripheralbloodDC浙江大学医学免疫学免疫11anLocatedinlymphfollicleswhicharerichinBcells;nDerivedfrominterstitialDC;nHighlyexpressFcR,CR1andCR2;nInvolvedinthegenerationandmaintenanceofmemoryBcells.1)FollicularDC(FDC)1)FollicularDC(FDC)浙江大学医学免疫学免疫1
11、1aFollicularDC,FDCFollicularDC,FDCBcellsFDCFDCexpresshighlevelsofmembranereceptorsforantibodyandcomplement.Bythese,FDCactivestheBcellsinlymphnodes.浙江大学医学免疫学免疫11a2)InterdigitatingDC(IDC)2)InterdigitatingDC(IDC)nMainAPCtoinduceprimaryimmuneresponse;nDerivedfromLangerhanscells;nFcR-andC3bR-,MHCIandIIhi
12、gh;nDistributedmainlyintheTcellareaofsecondarylymphoidtissue,presentAgstoTcells.浙江大学医学免疫学免疫11a3)Langerhanscells(LC)3)Langerhanscells(LC)nFoundintheepidermis(skin)andmucousmembranes;nMHCIandIIhigh,highlyexpressFcRandC3bR,Birbeckparticle(duetolangerinexpression);nPowerfulabilitytocaptureandprocessAgsa
13、ndmigrationtolymphnodeafteractivation.LangerhansIDCLangerhansIDC浙江大学医学免疫学免疫11a4.DevelopmentofmyeloidDC4.DevelopmentofmyeloidDCnFourphasesFourphasesnPre-DCPre-DCnMonocyte,MoMonocyte,MonImmatureDCImmatureDCnUptakeantigenUptakeantigennMigrationMigrationnMatureDCMatureDCnExpresshighlevelsofMHCIandII,CD8
14、0,CD86,ExpresshighlevelsofMHCIandII,CD80,CD86,CD40,CD54,HSP,etc.CD40,CD54,HSP,etc.浙江大学医学免疫学免疫11anImmatureDCPhenotype:highexpressionofreceptorsrelatedtophagocytosis(FcR,CR,mannosereceptor,DC-sign);lowexpressionofCD54,CD40,CD80;CD86andMHCII,CD14-Function:1)strongcapacitytoingestandprocessAgs,butweakab
15、ilitytopresentAgs2)inductionofimmunetolerance3)sensingofinfectiousagentsbyTLR(patternrecognitionreceptors)浙江大学医学免疫学免疫11anMatureDCPhenotype:lowexpressionofreceptorsrelatedtophagocytosis(FcR,CR,mannosereceptor);highexpressionofCD54,CD40,CD80,CD86andMHCII;CD83+andCD25+Function:weakabilitytocaptureandpr
16、ocessAgs,powerfulabilitytopresentAgs.浙江大学医学免疫学免疫11aDendriticCellMaturationDendriticCellMaturationMHCIIMHCII浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a5.DCinimmuneactivationand5.DCinimmuneactivationandimmunetoleranceimmunetolerance1)DCinimmuneactivation1)DCinimmuneactivationPresentantigenandactivateTcellsPresentant
17、igenandactivateTcellsThefirstsignalMHCII-Ag:CD4ThefirstsignalMHCII-Ag:CD4+ +TcellsTcellsMHCI-Ag:CD8MHCI-Ag:CD8+ +TcellsTcellsThesecondsignalThesecondsignalco-stimulatingmoleculesco-stimulatingmoleculescytokinesIL-12cytokinesIL-12浙江大学医学免疫学免疫11an Peripheraltolerance:Peripheraltolerance:immatureDCimmat
18、ureDCcaptureautoantigenwhentheymigratecaptureautoantigenwhentheymigratefromnon-lymphoidtissuetoTcellareafromnon-lymphoidtissuetoTcellareaofsecondarylymphoidtissue,andofsecondarylymphoidtissue,andinduceperipheraltolerance.induceperipheraltolerance.nCentraltolerance:Centraltolerance:inducedinnegativei
19、nducedinnegativeselectionofTcellsinthethymus.selectionofTcellsinthethymus.n 2)DCinduceimmunetolerance2)DCinduceimmunetolerance浙江大学医学免疫学免疫11a Bone marrow Blood TissueHSCMyeloid progenitorPre-monocyteMonocyte Monocyte Macrophage IIMononuclearphagocytesystem(MPS)IIMononuclearphagocytesystem(MPS) 1.Diff
20、erentiationanddistribution1.Differentiationanddistribution浙江大学医学免疫学免疫11aDifferentnamesindifferenttissuesnMonocyte(blood)nKupffercells(liver)nMesangialcells(kidneyglomerulus)nMicroglia(brain)nAlveolarmacrophages(lung)nHistiocyte(connectivetissue)浙江大学医学免疫学免疫11anMHC-IandMHC-IandIImolecules;IImolecules;
21、nCAM:LFA-1,ICAM-1,B7,CD40;CAM:LFA-1,ICAM-1,B7,CD40;nFcR;FcR;nCR:CR1,CR3,CR4;CR:CR1,CR3,CR4;nPattern-recognitionreceptor(PRR):mannosePattern-recognitionreceptor(PRR):mannosereceptor,scavengerreceptor(CD91),Toll-likereceptor,scavengerreceptor(CD91),Toll-likereceptorsreceptors2. 2. SurfacemarkersSurfac
22、emarkers浙江大学医学免疫学免疫11a3.3.BiologicalfunctionsofMBiologicalfunctionsofM AntigenprocessingandpresentationAntigenprocessingandpresentationphagocytosisphagocytosispinocytosispinocytosisreceptor-mediatedendocytosisreceptor-mediatedendocytosis浙江大学医学免疫学免疫11a AntimicrobialandcytotoxicactivityAntimicrobialan
23、dcytotoxicactivity:a:anumberofantimicrobialandcytotoxicnumberofantimicrobialandcytotoxicsubstancesproducedbyactivatedMsubstancesproducedbyactivatedM candestroyphagocytosedmicroorganisms.candestroyphagocytosedmicroorganisms. Reactiveoxygenintermediates,nitricoxide.Reactiveoxygenintermediates,nitricox
24、ide. 浙江大学医学免疫学免疫11anSecretionofsolublefactors:Secretionofsolublefactors: enzymes:lysozyme,myeloperoxidase,etc.enzymes:lysozyme,myeloperoxidase,etc.cytokines:IL-1,IL-6,TNF,IL-12,IL-18,etc.cytokines:IL-1,IL-6,TNF,IL-12,IL-18,plement:C1complement:C1C9,BfC9,Bfcoagulationfactors,PG,LTs,ACTH,etc.coagulati
25、onfactors,PG,LTs,ACTH,etc.浙江大学医学免疫学免疫11aphagocytosisphagocytosis浙江大学医学免疫学免疫11amacrophage浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11aAgpresentationAgpresentation浙江大学医学免疫学免疫11aIII.BcellsIII.Bcellsbonemarrow-dependentlymphocyteAbout5-15%ofthecirculatinglymphoidpoolareBcellsdefinedbythepresenceofsurfaceim
26、munoglobulin(Ig).浙江大学医学免疫学免疫11aIII.BcellsIII.Bcells浙江大学医学免疫学免疫11aAntigenprocessingandAntigenprocessingandpresentationpresentation浙江大学医学免疫学免疫11a1.Bindinganduptakeofantigenndependsonthephysicalstateoftheantigenandthecelltypeinvolved.2.AntigenprocessingnMHCclassIprocessingpathwaynMHCclassIIprocessingpa
27、thway3.Antigenpresentation浙江大学医学免疫学免疫11a1BindinganduptakeofantigenBindinganduptakeofantigennEndogenousantigens:MHCI-CD8nProducedwithinthecells,SuchasviralproteinsortumorproteinsnprocessedbyhostcellnExogenousantigens:MHCII-CD4nProducedoutofthecells,Bacteria,cellsandsolubleproteinsnprocessedbyAPC浙江大学医
28、学免疫学免疫11a浙江大学医学免疫学免疫11aUptakeantigenbyimmatureDCandUptakeantigenbyimmatureDCandmacrophagemacrophagenPinocytosisnLiquidorsmallgranulenPhagocytosisLargemolecularormicrobenReceptor-mediatedendocytosisneffectivenSelective浙江大学医学免疫学免疫11annonspecificallyengulfednBCR-mediatedUptakeantigenbyBcellsUptakeantig
29、enbyBcells浙江大学医学免疫学免疫11a2 2AntigenprocessingAntigenprocessingnDegradationofexternally-orinternally-derivedantigenintoshortpeptidesequencesnAssociation of the peptide with MHCmolecules浙江大学医学免疫学免疫11a1.ThepathwayofMHCI-associated1.ThepathwayofMHCI-associatedendogenousAgpresentationendogenousAgpresentat
30、iontransportedtotransportedtoendoplasmicendoplasmicreticulumreticulumbyTAPbyTAPdegradedbyproteasome(LMP2/7)degradedbyproteasome(LMP2/7)incytoplasmincytoplasmendogenousantigen(suchasvirusAg,tumorAg)endogenousantigen(suchasvirusAg,tumorAg) antigenpeptideantigenpeptide（8-10aa8-10aa） Peptide/MHC-Imolecu
31、lecomplexPeptide/MHC-ImoleculecomplextosurfaceofAPCtosurfaceofAPCpresenttoCD8presenttoCD8+ +T Tkilltheinfectedormutatedcellskilltheinfectedormutatedcells浙江大学医学免疫学免疫11aDegradation in the proteasomeThe components of the proteasome include MECL-1, LMP2, LMP7.Protein in cells including non-self proteins
32、are degraded continuously by a multicatalytic protease of 28 subunits浙江大学医学免疫学免疫11aProteasome,theCytosolicMeatProteasome,theCytosolicMeatGrinderThatChopsUpProteinsGrinderThatChopsUpProteins浙江大学医学免疫学免疫11aENDOPLASMIC RETICULUMCYTOSOLPeptideantigensproducedinthecytoplasmarephysicallyPeptideantigensprod
33、ucedinthecytoplasmarephysicallyseparatedfromnewlyformedMHCclassIseparatedfromnewlyformedMHCclassINewly synthesisedMHC class I moleculesPeptides needaccess to the ER inorder to be loaded onto MHC class I moleculesLMPLMPTAPTAP浙江大学医学免疫学免疫11aER membraneLumen of ERCytosolTransporter-associated withantige
34、n processing (TAP1 & 2)Transporter has preference for 8 amino acid peptideswith hydrophobic C termini.TAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideER membraneLumen of ERCytoso
35、lTAP-1TAP-2PeptideATP-binding cassette(ABC) domainHydrophobictransmembranedomainPeptide antigensfrom proteasome浙江大学医学免疫学免疫11aEndoplasmic reticulumCalnexin bindsto nascentclass I chainuntil 2-M bindsTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2Peptide
36、TAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2Peptide2-M binds and stabilises floppy MHCTapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHCCytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compactMaturation and loading of
37、MHC class I浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a2.ThepathwayofMHCII-associatedexogenousAg2.ThepathwayofMHCII-associatedexogenousAgpresentationpresentationExogenous antigen newly synthesised MHC class II molecule (in the endoplasmic reticulum) endosome Ii binds in the groove of MHC
38、 class II molecule lysosome protease M II C phagolysosome li CLIP protease DMDegrade into 12 15aa peptide + releasing the CLIP and allowing other peptide to bind Ag peptide/MHC class II molecule complextransport to the surface of APC, recognized by CD4+TPhagocytosis,pinocytosis,Phagocytosis,pinocyto
39、sis,FcR-phagocytosisBCR-FcR-phagocytosisBCR-receptorreceptor浙江大学医学免疫学免疫11aYYPinocytosisPhagocytosisMembrane Igreceptor mediateduptakeYUptake of exogenous antigensComplement receptormediated phagocytosisYFc receptor mediated phagocytosisopsonization浙江大学医学免疫学免疫11aProteases produce 24 amino acid long p
40、eptides from antigensEndosomesExogenouspathwayExogenouspathwayIncreasein acidityCell surfaceTo lysosomesUptakeProtein antigensIn endosomeCathepsin B, D and L proteases are activated by the decrease in pH浙江大学医学免疫学免疫11aNeed to prevent newly synthesised, unfolded self proteins from binding to immature
41、MHC Invariant chain stabilises MHC class II by non-covalently binding to the immature MHC class II molecule and forming a nonomeric complexIn the endoplasmic reticulumMHCclassIImaturationandinvariantchainMHCclassIImaturationandinvariantchain浙江大学医学免疫学免疫11a involve in the assembling and folding of MHC
42、 class II molecule; Block the groove of MHC class II molecule; Lead the assembled class II molecule to M II C.ThefunctionsofIi:ThefunctionsofIi:CLIP：class II-associated invariant chain peptide浙江大学医学免疫学免疫11aHLA-DMcatalysestheremovalofCLIPHLA-DMcatalysestheremovalofCLIPMIIC compartmentHLA-DMReplaces C
43、LIP with a peptide antigen using a catalytic mechanism (i.e. efficient at sub-stoichiometric levels)Discovered using mutant cell lines that failed to present antigenHLA-DO may also play a role in peptide exchangeSequence in cytoplasmic tail retains HLA-DM in endosomesHLA-DMHLA-DR浙江大学医学免疫学免疫11aMIIC c
44、ompartment sorts peptide-MHC complexes for surface expression orlysosomal degradationSurfaceexpressionofMHCclassII-SurfaceexpressionofMHCclassII-peptidecomplexespeptidecomplexesExported to the cell surfaceSent to lysosomes for degradation 浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11aImpor
45、tantaspectsofAgprocessingImportantaspectsofAgprocessingnLocationofpathogendictatestypeofresponseVirusincytosolMHCclassIpathwayCTLExtracellularpathogenMHCclassIIpathwayCD4responseAbproductioncytokineproduction浙江大学医学免疫学免疫11aSamplequestionSamplequestion1.ProductsofTAP-1andTAP-2genesA.Bind 2m.B.Preventp
46、eptidebindingtoMHCmolecules.C.Arepartoftheproteasome.D.TransportpeptidesintotheendoplasmicreticulumforbindingtoMHCclassI.E.TransportpeptidesintoendoplasmicreticulumforbindingtoMHCclassII.Answer=DAnswer=D浙江大学医学免疫学免疫11a2.Whichofthefollowingcellsisprofessionalantigen-2.Whichofthefollowingcellsisprofess
47、ionalantigen-presentingcell?-()presentingcell?-()A.DendriticcellsB.EndothelialcellsC.NeutrophilsD.TcellsE.MastcellsAnswer=AAnswer=A浙江大学医学免疫学免疫11a3.Whichofthefollowinggeneproductsisinvolvedinthe3.WhichofthefollowinggeneproductsisinvolvedinthepathwayofMHCclassIassociateendogenousantigenpathwayofMHCcla
48、ssIassociateendogenousantigenpresentation?()presentation?()A.LMP2/7B.IiC.HLA-DMD.HLA-DOE.HLA-DR3Answer=AAnswer=A浙江大学医学免疫学免疫11aReviewquestionsnWhatarethedifferencesbetweenimmatureDCandmatureDC?nDescribethepathwayofMHCI-associatedendogenousAgpresentationandMHCII-associatedexogenousAgpresentation.浙江大学医学免疫学免疫11aThanksforyourattention!浙江大学医学免疫学免疫11a浙江大学医学免疫学免疫11a
