免疫细胞和免疫应答ppt课件

Immunocytes,InstituteofImmunologyMedicalSchoolofZhejiangUniversityJianzhongChen(陈建忠office)chenjianzhong,1,Cellsofimmunesystem,2,Tlymphocytes,3,DevelopmentofTcells,4,StagesofTcellmaturation,5,Positiveandnegativeselection,Positiveselection（阳性选择）DPcellsthatbind,withmoderateaffinity,toMHC-Agonthymicstromacellssurvive-MHCrestriction（MHC限制性）MHCI-CD8+TcellsMHCII-CD4+TcellsNegativeselection（阴性选择）CellsthatbindtoMHC-Agonthymicstromacells(orauto-reactiveTcells,ART)willundergoapoptosisFormationofcentralimmunetolerance（免疫耐受）,6,7,Tcellsurfacemarkers,8,TCR-CD3complexTCRAheterodimercomprisinganandachainoraandachainjoinedbyadisulfidebond.Function:specificrecognitionofpeptide-MHCcomplex.,9,TCR-CD3complex,10,Consistsof5proteinsthataredesignatedas,and.Threedimers:,()ThecytoplasmicdomaincontainsITAM(immunoreceptortyrosine-basedactivationmotif)YXXL/VFunction:transductionofsignalsthatleadtoTcellactivation.,CD3,11,Mainco-stimulatorymoleculesmediatinginteractionsbetweenTcellsandAPCs,12,Receptorsofmitogens(丝裂原受体),PHA-RConA-RPWM-RCytokinereceptor(细胞因子受体)Virusreceptor(病毒受体),13,Leukocytedifferentiationantigen(LDA，白细胞分化抗原):Thecellsurfacemarkerswhichexpressordisappearonthedifferentleukocytesinthedifferentstageofdifferentiationandactivation.,14,TCellSurfaceMolecules,CD(clusterofdifferentiation，分化群):Cellsurfacemoleculesofleucocytesthataredistinguishablewithmonoclonalantibodiesasanimmunologicmarker.CD1-350,15,CD4andCD8(coreceptor),Function:1)HelptheinteractionbetweenTcellandAPCandenhancetherecognitionofantigenbyTCR;2)helptheTCR-CD3signalstransductionCD4:MHCIIAgbinding,ReceptorofHIVgp120CD8:MHCIAgbinding,16,Co-stimulatorymolecules,CD28:itsligandsareB7familymolecules,includingB7-1/2(CD80/CD86)Function:costimulation,activationofTcellsCTLA-4(CD152):homodimer,homologoustoCD28.Function:inhibitsTcellcostimulation(thecytoplasmicdomaincontainsITIM),17,2005Elsevier,18,Celladhesionmolecules(细胞粘附分子),CAM:Agroupofproteinsinvolvedinadhesionofcelltocellorcelltoextra-cellularmatrix(ECM),suchasICAM-1,ICAM-2,ICAM-3,VCAM-1andPECAMetc.,19,CategoriesofCAM,1.Integrinfamily（整合素家族）2.Selectinfamily（选择素家族）3.Cadherin（钙粘素家族）4.IGSF(Igsuperfamily)（免疫球蛋白超家族）5.Mucin-likefamily（黏蛋白样家族）6.Others:PNAd,CD44,CD36,20,III.Tcellsubsets,1TCRTcellsandTCRTcells2CD4+TandCD8+Tcells3Th,TcandTreg4.NaiveTcells（初始型）,effectorTcells（效应性）andmemoryTcells（记忆性）,21,22,IV.FunctionsofTcells,1.CD4+helperTcells(Th)Th0:Thcellsthatsecretebroadspectrumofcytokinesatlowlevel.Th1:produceIL-2andIFN-,butnotIL-4.Theyarechieflyresponsibleforcell-mediatedimmuneresponses,butcanalsohelpBcellstoproduceIgG2a,butnotmuchIgG1orIgE;Th2:secreteIL-4,5,10,13,butnotIL-2andIFN-,areveryefficienthelpercellsforproductionofantibody,especiallyofIgG1andIgE;,23,24,25,IV.FunctionsofTcells,1.CD4+helperTcells(Th)Th3:produceTGF-.inhibitTh1mediatedimmunityandinflamationinhibitfunctionofB,Tc,NKTh17:secreteIL-17.innateimmunityandinflammation,26,2.CD8+cytotoxicTcells(CTL,Tc),Function:directlykilltargetcells(cytotoxicity)Mechanisms:,27,3.CD4+CD25+regulatoryTcells(Tr),Foxp3positiveFunction:Down-regulationofimmuneresponsebyinhibitingtheactivationandproliferationofCD4+orCD8+Tcells.Mechanisms:Directinhibitionbycontactingtargetcells.Inhibitorycytokines:IL-10,TGF-,etal.,28,2005Elsevier,29,Bcell,30,I.DevelopmentofBcell,BlymphocytesrefertoBonemarrow-derivedlymphocytesorBursa-derivedlymphocytesAbout20ofthecirculatinglymphoidpoolareBcells.,31,DevelopmentofBcellinBM,32,.B-cellsurfacemarkers,33,1.BCRcomplex,BCR(mIg)：VH,VL-AgmatureBcells:mIgMandmIgD.Function:specificallyrecognizesantigen.Ig/Ig(CD79a/CD79b):heterodimercytoplasmicdomainscontainITAM.Function:1.transfersthesignalsthatleadtoBcellactivation.2.transportstheIg,34,2.Co-receptors:CD19/CD21/CD81complex,35,3.Co-stimulatorymolecules(1)CD40(2)CD80/CD86(3)ICAM-1,LFA-1,36,4.OtherreceptorsCD20:BcellmarkerCD22:inhibitoryreceptorCD32:FcR,37,38,B-cellsubsets,B1cells(CD5+):ManyofthefirstBcellsthatappearduringontogenyexpressCD5,amarkeroriginallyfoundonTcells.(expressmIgM,nomIgD).TheyrespondwelltoTI-AgandmayalsobeinvolvedintheAgprocessingandpresentationtoTcells.Fduceanti-bacterialIgMthefirstlineofdefenceagainstmicroorganisms;2.producepolyreactiveAbclearanceofdenaturedselfcomponents;3.produceauto-Ab,therebyparticipatinginthepathogenesisofsomeautoimmunediseases.,39,B2cell:CD5-Bcells.mIg:IgM,IgDafterantigenicstimulation,inthepresenceofTh,theyproducemoreIgGthanIgM,40,B1andB2cell,41,NKCells,42,NKcellsweredefinedinitiallybytheirabilitytolysecertaintumorcelllinesandvirallyinfectedcellswithoutpriorimmunization,andsomediateaformofinnate(ornatural)immunitythatistermed“naturalkilling”.,43,I.OntogenyanddistributionofNKcell,Derivefromabonemarrowprecursorlargegranularlymphocytesdistribution:peripheralblood,spleenNKcellsarerareinlymphnodeanddonotcirculatethroughthelymph.,44,II.Surfacemarkers,1.CD562.CD16(FcRIII):ADCC3.CD24.CD11a/CD18(LFA-1)TheyneverthelessservetoidentifyNKcells,whicharegenerallyCD16+,CD56+,CD3-,whereasTcellsareCD16-,CD56-,CD3+.,45,5.NKcellsreceptors,KAR(killercellactivationreceptor，杀伤细胞活化受体):CD94/NKG2CITAM(immnoreceptortyrosine-basedactivationmotif,-YxxL/Vx(7-11)YxxL/V-)ligand:saccharideKIR(killercellinhibitoryreceptor，杀伤细胞抑制受体):CD94/NKG2AITIM(immnoreceptortyrosine-basedinhibitorymotif,I/VxYxxL)ligand:classIMHCmoleculesIntracellularsignalingpathwayscoordinateinhibitoryandactivatingsignals,46,Downloadedfrom:StudentConsult(on1June200601:58PM),2005Elsevier,47,III.FunctionsofNKcells,1.Anti-infectionprovideanearlyinnatebarriertoinfectionbyeliminatinginfectedhostcell2.Anti-tumorkilltumorcellsdirectly:perforin,granularenzymeADCC3.ImmunoregulationproducecytokinessuchasIFN-,TNF-,G-CSF,48,Antigen-presentingcells抗原提呈细胞,49,ProfessionalAPCs:Dendriticcells;Monocytes/macrophagesandBcells,ClassificationofAPCs,50,ClassificationofAPCs,Non-professionalAPC,Endothelialcell(EC)FibroblasticcellActivatedTcell,InducibleexpressionofMHCclassIImolecules,Targetcells,ExpressionofMHCclassImolecules,51,Bonemarrow,Blood,Tissue,HSC,Myeloidprogenitor,Pre-monocyte,Monocyte,Monocyte,Macrophage,IIMonocytesandmacrophages1.Differentiationanddistribution,52,MHC-IandIImolecules;CAM:LFA-1,ICAM-1,B7,CD40;CKR:M-CSFR;FcR;CR:CR1,CR3,CR4;Pattern-recognitionreceptor(PRR):mannosereceptor,scavengerreceptor,Toll-likereceptor,2.Surfacemarkers,53,3.BiologicalfunctionsofM,(1)Phagocytosisandcytotoxicactivity:chemotaxis:blood-tissueopsonization:Ig,C3b,C4banumberofantimicrobialandcytotoxicsubstancesproducedbyactivatedMcandestroyphagocytosedmicroorganisms.Reactiveoxygenintermediates,NO,proteinases.,54,phagocytosis,55,(2)Antigenprocessingandpresentation:phagocytosispinocytosisreceptor-mediatedendocytosis,56,(3)Secretionofsolublefactorstoregulateimmuneresponseenzymes:lysozyme,myeloperoxidase,etc.cytokines:IL-1,IL-6,TNF,IL-12,IL-18,plement:C1C9,Bfcoagulationfactor,PG,LTs,ACTH,etc.,57,Dendriticcells(DCs，树突状细胞),58,1.Surfacemarkers,(1)MHCclassIImolecule(2)Specificmarks:CD1a,CD11c,CD83(human);33D1,NLDC145(mouse)(3)Co-stimulatorymolecules:CD80,CD86,CD40,CD44,CD54,integrin1,2(4)Receptor:FcR,TLR,59,2.ClassificationofDC:originofDC,HSC,Myeloidprogenitor,Lymphoidprogenitor,MyeloidDC,Mo,macrophage,MyeloidDC,PMN,LymphoidDC,60,2.ClassificationofDC:,61,DendriticCellMaturation,62,MigratingDC,63,2.ClassificationofDC:distribution,LymphoidtissueDCfollicularDC(FDC),interdigitatingDC(IDC),thymicDCNon-lymphoidtissueDCLangerhanscell,interstitialDCCirculatingDCperipheralbloodDC,veiledcell,64,4.FunctionofDC,AntigenpresentingandactivationofadaptiveTcellsImmunoregulationMaintainanceandinductionofimmunetolerance,65,Bcells,66,67,ImmuneResponse免疫应答,68,ImmuneResponse（免疫应答）,innateimmuneresponse(固有免疫应答)naturalimmuneresponsenon-specificimmuneresponseadaptiveimmuneresponse（适应性免疫应答）acquiredimmuneresponsespecificimmuneresponse,69,Innateandadaptiveimmunity,70,innateimmuneresponse,PhysiologicalbarriersskinmucousmembranesPhagocytosispolymorphonuclearleukocytes(PMN)macrophagesToll-likereceptor4/LPSNaturalkiller(NK)cellComplement,Acutephaseproteins,71,innateimmuneresponse,72,innateimmuneresponse,73,Adaptiveimmuneresponse,74,ImmuneResponse,75,FeaturesofInnateandAdaptiveImmunity,76,Tcell-mediatedimmuneresponse,77,TypesofintracellularmicrobescombatedbyTcell-mediatedimmunity,78,PhasesofTcellresponses,ThreephasesAntigenrecognitionphaseActivation,proliferationanddifferentiationphaseEffectorphase,79,80,81,.Antigenrecognition,1AgpresentationbyAPC,82,Antigenprocessingandpresentation,83,I.Uptakeofantigens,84,Y,Thesiteofpathogenreplicationormechanismofantigenuptakedeterminestheantigenprocessingpathwayused,CytosoliccompartmentEndogenousprocessing(Viralantigens),VesicularCompartmentContiguouswithextracellularfluidExogenousprocessing(Streptococcal,Mycobacterialantigens),DistinctmechanismsofantigengenerationareusedtoraiseTcellssuitedtotheeliminationofendogenousorexogenouspathogens,INTRACELLULARREPLICATION,EXTRACELLULARORENDOSOMALREPLICATION,85,86,1.ThepathwayofMHCI-associatedendogenousAgpresentation,endogenousantigen(suchasvirusAg,tumorAg)antigenpeptide（8-13aa）Peptide/MHC-ImoleculecomplextosurfaceofAPCsubmittoCD8+T,transportedtoendoplasmicreticulumbyTAP,degradedbyproteasome(LMP)incytoplasm,87,Degradationintheproteasome,ThecomponentsoftheproteasomeincludeMECL-1,LMP2,LMP7.ThesecomponentsareinducedbyIFN-andreplaceconstitutivecomponentstoconferproteolyticproperties.LMP2BlockthegrooveofMHCclassIImolecule;LeadtheassembledclassIImoleculetoMIIC.,ThefunctionsofIi:,CLIP：classII-associatedinvariantchainpeptide,99,ClassII-associatedinvariantchainpeptide(CLIP),(-Ii)3complexesdirectedtowardsendosomesbyinvariantchain,proteasedegradesInvariantchainCLIPblocksgrooveinMHCmolecule,MHCClassIIcontainingvesiclesfusewithantigencontainingvesicles,100,HLA-DMcatalysestheremovalofCLIP,MIICcompartment,HLA-DMReplacesCLIPwithapeptideantigenusingacatalyticmechanism(i.e.efficientatsub-stoichiometriclevels)DiscoveredusingmutantcelllinesthatfailedtopresentantigenHLA-DOmayalsoplayaroleinpeptideexchange,101,MIICcompartmentsortspeptide-MHCcomplexesforsurfaceexpressionorlysosomaldegradation,SurfaceexpressionofMHCclassII-peptidecomplexes,102,MHC-IIGoesfromGolgi(G)toMHC-IICompartment(MIIC)WherePeptideLoadingOccurs,103,104,105,106,3.Cross-presentation,ClassIMHCmoleculespresentexogenousAgstoCD8+TcellsCross-presentationofAgsbyDCplaysanimportantroleinanti-viralinfectionandanti-tumorimmunity.,107,3.Cross-presentation,108,4,CD1-mediatedantigenpresentingpathway,109,110,2,InteractionbetweenAPCandTcell,NonspecificbindingofAPCandTcellSpecificbindingofAPCandTcellTCR-peptide-MHCco-receptor-MHCco-stimulatorymoleculesTcellsynapseorimmunologicalsynapse,111,Ligand-receptorpairsinvolvedinTcellactivation,112,MaincostimulatorymoleculesmediatinginteractionsbetweenTcellsandAPCs,113,3activation,proliferationanddifferentiation,ThefirstsignalTCR-antigenpeptide-MHC(doublerecognition)CD4-MHCIIorCD8-MHCIThesecondsignal(co-stimulatorysignal)Interactionsbetweenco-stimulatorymoleculesonAPCandcorrespondingreceptorsonTcellsCD28/CTLA-4B7,LFA-1ICAM-1,LFA-2LFA-3CytokinesinTcellactivationIL-1,2,6,12,114,115,ProliferationanddifferentiationofTcells,1)CD4+Tcells:Th,Tr,Treg,Th17,Tmregulatedbycytokines2)CD8+Tcells:TcTh-dependentTh-independent:virusinfectedDCthathighlyexpressco-stimulatorymoleculescandirectlystimulateCD8+Tcells.,116,ActivationofCD8+Tcells,117,CytokinesarerequiredinTcellproliferationanddifferentiation,ActivatedTcellscanproducecytokines(IL-2,4,7,10,etc.)andexpresscytokinereceptors,thatpromoteTcellstoproliferateanddifferentiate.,118,4.EffectorfunctionsofactivatedTcells,1)CD4+TcellsTh1:secreteIFN-,etc.expressCD40LexpressFasL,killFas+targetcellseffectonlymphocytes:IL-2effectonneutrophil:TNF-,Th2:promoteBcellgrowthandIgproductionmediatehypersensitivityTh17:IL-17,Il-8,TNF-:enhanceleukocyterecruitmentandinflammation,Activatemacrophages,119,Twotypesofcell-mediatedimmunity,120,Cell-mediatedimmunityagainstintracellularmicrobes,121,ActivationofmacrophagesbyTlymphocytes,122,Cytotoxicity:killtargetcellsa.necrosis:perforinandgranzymeb.apoptosis:granzyme,FasLCharacteristicsofCD8+Tcellcytotoxicitya.Specificityb.MHCIrestrictionc.Highefficiency,2)CD8+Tcells,123,Downloadedfrom:StudentConsult(on1June200603:50PM),2005Elsevier,MechanismsofkillingofinfectedcellsbyCD8+CTLs,124,125,3)memoryTcells,1)CD45RA-CD45RO+,2)Long-livedmemorytospecificantigen3)Mediatefaster,strongerandmoreeffectiveimmuneresponse4)Mechanism:lowdependentoncostimulatorymoleculesormoresensitivitytocytokines,126,Activationinducedcelldeath,AICD,1)ActivationinducedcelldeathActivatedTcellsexpressFasLthatinduceapoptosisofFaspositiveTcells.2)PassivecellapoptosisAg,survivalsignalsandgrowthfactors,127,Activation-induceddeathofTcells,128,Bcell-mediatedhumoralimmuneresponse,Humoralimmunityismediatedbyantibodiesandisthearmoftheadaptiveimmuneresponsethatfunctionstoneutralizeandeliminateextracellularmicrobesandmicrobialtoxins.,129,Phasesandtypesofhumoralimmuneresponses,1)PhasesAntigenrecognitionphaseActivation,proliferationanddifferentiationphaseEffectorphase2)TypesResponsetoTD-AgResponsetoTI-Ag,130,Phasesofhumoralimmuneresponses,Effectorphase,131,1)BcellsrecognizeTD-Aga.BCRdirectlyrecognizesBcellepitopesb.Ig/Igtransferthefirstsignalc.Effectofcoreceptors(CD21/CD19/CD81)d.Signallingpathways,132,Theroleofcoreceptor(CD19/CD21/CD81)inBcellactivation,133,2)RoleofThcellsinhumoralimmuneresponsetoTD-Ag,ForaproteinAgtostimulateAbresponse,BcellsandThcellsspecificforthatAgmustcometogetherinlymphoidorgansandinteractinawaythatstimulatesBcellproliferationanddifferentiation.,134,a.ActivationandmigrationofhelperTcells,Thcellsthathavebeenactivatedtodifferentiateintoeffectorcellsinteractwithantigen-stimulatedBcellsattheedgesoflymphoidfolliclesintheperipherallymphoidorgans.,135,TheinteractionsofThcellsandBcellsinlymphoidtissues.,136,b.PresentationofAgsbyBcellstoThcells,BcellsthatbindproteinAgsbytheirBCRendocytosetheseAgs,processtheminendosomalvesicles,displayMHCII-peptidesforrecognitionofThcells.BcellsandThcellsrecognizedifferentepitopesofthesameproteinAg.,137,AgpresentationbyBcellstoThcells,138,139,c.MechanismsofThcell-mediatedactivationofBcells,ThcellsthatrecognizeAgpresentedbyBcellsactivatedBcellbyexpressingCD40Landbysecretingcytokines(IL-2,IFN-,IL-4,IL-5,IL-6,IL-13,etc.).,140,Downloadedfrom:StudentConsult(on1June200603:50PM),2005Elsevier,MechanismsofThcell-mediatedactivationofBcells,141,Theanatomyofhumoralimmuneresponses,142,2)BcellmaturationinGerminalcenter,Hypermutation（超突变）AffinityMaturation(亲和力成熟)Receptorediting(受体编辑)ClassSwitch（抗体类别转换）,143,AffinitymaturationinAbresponses,AffinitymaturationistheprocessbywhichtheaffinityofAbsproducedinresponsetoaproteinAgincreaseswithprolongedandrepeatedexposuretothatAg.TheincreaseinaffinityisduetopointmutationsintheVregions,andparticularlyintheAg-bindingHVR,oftheAbspro