免疫细胞和免疫应答.ppt

Immunocytes InstituteofImmunologyMedicalSchoolofZhejiangUniversityJianzhongChen 陈建忠 0571 88208286 office chenjianzhong Cellsofimmunesystem Tlymphocytes DevelopmentofTcells StagesofTcellmaturation 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 Tcellsurfacemarkers TCR CD3complexTCRAheterodimercomprisingan anda chainora anda chainjoinedbyadisulfidebond Function specificrecognitionofpeptide MHCcomplex TCR CD3complex Consistsof5proteinsthataredesignatedas and Threedimers ThecytoplasmicdomaincontainsITAM immunoreceptortyrosine basedactivationmotif YXXL VFunction transductionofsignalsthatleadtoTcellactivation CD3 Mainco stimulatorymoleculesmediatinginteractionsbetweenTcellsandAPCs Receptorsofmitogens 丝裂原受体 PHA RConA RPWM RCytokinereceptor 细胞因子受体 Virusreceptor 病毒受体 Leukocytedifferentiationantigen LDA 白细胞分化抗原 Thecellsurfacemarkerswhichexpressordisappearonthedifferentleukocytesinthedifferentstageofdifferentiationandactivation TCellSurfaceMolecules CD clusterofdifferentiation 分化群 Cellsurfacemoleculesofleucocytesthataredistinguishablewithmonoclonalantibodiesasanimmunologicmarker CD1 350 CD4andCD8 coreceptor Function 1 HelptheinteractionbetweenTcellandAPCandenhancetherecognitionofantigenbyTCR 2 helptheTCR CD3signalstransductionCD4 MHCIIAgbinding ReceptorofHIVgp120CD8 MHCIAgbinding Co stimulatorymolecules CD28 itsligandsareB7familymolecules includingB7 1 2 CD80 CD86 Function costimulation activationofTcellsCTLA 4 CD152 homodimer homologoustoCD28 Function inhibitsTcellcostimulation thecytoplasmicdomaincontainsITIM 2005Elsevier Celladhesionmolecules 细胞粘附分子 CAM Agroupofproteinsinvolvedinadhesionofcelltocellorcelltoextra cellularmatrix ECM suchasICAM 1 ICAM 2 ICAM 3 VCAM 1andPECAMetc 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 III Tcellsubsets 1 TCR TcellsandTCR Tcells2 CD4 TandCD8 Tcells3 Th TcandTreg4 NaiveTcells 初始型 effectorTcells 效应性 andmemoryTcells 记忆性 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 IV FunctionsofTcells 1 CD4 helperTcells Th Th3 produceTGF inhibitTh1mediatedimmunityandinflamationinhibitfunctionofB Tc NKTh17 secreteIL 17 innateimmunityandinflammation 2 CD8 cytotoxicTcells CTL Tc Function directlykilltargetcells cytotoxicity Mechanisms 3 CD4 CD25 regulatoryTcells Tr Foxp3positiveFunction Down regulationofimmuneresponsebyinhibitingtheactivationandproliferationofCD4 orCD8 Tcells Mechanisms Directinhibitionbycontactingtargetcells Inhibitorycytokines IL 10 TGF etal 2005Elsevier Bcell I DevelopmentofBcell BlymphocytesrefertoBonemarrow derivedlymphocytesorBursa derivedlymphocytesAbout20 ofthecirculatinglymphoidpoolareBcells DevelopmentofBcellinBM B cellsurfacemarkers 1 BCRcomplex BCR mIg VH VL AgmatureBcells mIgMandmIgD Function specificallyrecognizesantigen Ig Ig CD79a CD79b heterodimercytoplasmicdomainscontainITAM Function 1 transfersthesignalsthatleadtoBcellactivation 2 transportstheIg 2 Co receptors CD19 CD21 CD81complex 3 Co stimulatorymolecules 1 CD40 2 CD80 CD86 3 ICAM 1 LFA 1 4 OtherreceptorsCD20 BcellmarkerCD22 inhibitoryreceptorCD32 Fc R B cellsubsets B1cells CD5 ManyofthefirstBcellsthatappearduringontogenyexpressCD5 amarkeroriginallyfoundonTcells expressmIgM nomIgD TheyrespondwelltoTI AgandmayalsobeinvolvedintheAgprocessingandpresentationtoTcells Functions1 produceanti bacterialIgMthefirstlineofdefenceagainstmicroorganisms 2 producepolyreactiveAbclearanceofdenaturedselfcomponents 3 produceauto Ab therebyparticipatinginthepathogenesisofsomeautoimmunediseases B2cell CD5 Bcells mIg IgM IgDafterantigenicstimulation inthepresenceofTh theyproducemoreIgGthanIgM B1andB2cell NKCells NKcellsweredefinedinitiallybytheirabilitytolysecertaintumorcelllinesandvirallyinfectedcellswithoutpriorimmunization andsomediateaformofinnate ornatural immunitythatistermed naturalkilling I OntogenyanddistributionofNKcell Derivefromabonemarrowprecursorlargegranularlymphocytesdistribution peripheralblood spleenNKcellsarerareinlymphnodeanddonotcirculatethroughthelymph II Surfacemarkers 1 CD562 CD16 Fc RIII ADCC3 CD24 CD11a CD18 LFA 1 TheyneverthelessservetoidentifyNKcells whicharegenerallyCD16 CD56 CD3 whereasTcellsareCD16 CD56 CD3 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 Downloadedfrom StudentConsult on1June200601 58PM 2005Elsevier III FunctionsofNKcells 1 Anti infectionprovideanearlyinnatebarriertoinfectionbyeliminatinginfectedhostcell2 Anti tumorkilltumorcellsdirectly perforin granularenzymeADCC3 ImmunoregulationproducecytokinessuchasIFN TNF G CSF Antigen presentingcells抗原提呈细胞 ProfessionalAPCs Dendriticcells Monocytes macrophagesandBcells ClassificationofAPCs ClassificationofAPCs Non professionalAPC Endothelialcell EC FibroblasticcellActivatedTcell InducibleexpressionofMHCclassIImolecules Targetcells ExpressionofMHCclassImolecules Bonemarrow Blood Tissue HSC Myeloidprogenitor Pre monocyte Monocyte Monocyte Macrophage IIMonocytesandmacrophages1 Differentiationanddistribution 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 3 BiologicalfunctionsofM 1 Phagocytosisandcytotoxicactivity chemotaxis blood tissueopsonization Ig C3b C4banumberofantimicrobialandcytotoxicsubstancesproducedbyactivatedM candestroyphagocytosedmicroorganisms Reactiveoxygenintermediates NO proteinases phagocytosis 2 Antigenprocessingandpresentation phagocytosispinocytosisreceptor mediatedendocytosis 3 Secretionofsolublefactorstoregulateimmuneresponseenzymes lysozyme myeloperoxidase etc cytokines IL 1 IL 6 TNF IL 12 IL 18 plement C1 C9 Bfcoagulationfactor PG LTs ACTH etc Dendriticcells DCs 树突状细胞 1 Surfacemarkers 1 MHCclassIImolecule 2 Specificmarks CD1a CD11c CD83 human 33D1 NLDC145 mouse 3 Co stimulatorymolecules CD80 CD86 CD40 CD44 CD54 integrin 1 2 4 Receptor FcR TLR 2 ClassificationofDC originofDC HSC Myeloidprogenitor Lymphoidprogenitor MyeloidDC Mo macrophage MyeloidDC PMN LymphoidDC 2 ClassificationofDC DendriticCellMaturation MigratingDC 2 ClassificationofDC distribution LymphoidtissueDCfollicularDC FDC interdigitatingDC IDC thymicDCNon lymphoidtissueDCLangerhanscell interstitialDCCirculatingDCperipheralbloodDC veiledcell 4 FunctionofDC AntigenpresentingandactivationofadaptiveTcellsImmunoregulationMaintainanceandinductionofimmunetolerance Bcells ImmuneResponse免疫应答 ImmuneResponse 免疫应答 innateimmuneresponse 固有免疫应答 naturalimmuneresponsenon specificimmuneresponseadaptiveimmuneresponse 适应性免疫应答 acquiredimmuneresponsespecificimmuneresponse Innateandadaptiveimmunity innateimmuneresponse PhysiologicalbarriersskinmucousmembranesPhagocytosispolymorphonuclearleukocytes PMN macrophagesToll likereceptor4 LPSNaturalkiller NK cellComplement Acutephaseproteins innateimmuneresponse innateimmuneresponse Adaptiveimmuneresponse ImmuneResponse FeaturesofInnateandAdaptiveImmunity Tcell mediatedimmuneresponse TypesofintracellularmicrobescombatedbyTcell mediatedimmunity PhasesofTcellresponses ThreephasesAntigenrecognitionphaseActivation proliferationanddifferentiationphaseEffectorphase Antigenrecognition 1AgpresentationbyAPC Antigenprocessingandpresentation I Uptakeofantigens Y Thesiteofpathogenreplicationormechanismofantigenuptakedeterminestheantigenprocessingpathwayused CytosoliccompartmentEndogenousprocessing Viralantigens VesicularCompartmentContiguouswithextracellularfluidExogenousprocessing Streptococcal Mycobacterialantigens DistinctmechanismsofantigengenerationareusedtoraiseTcellssuitedtotheeliminationofendogenousorexogenouspathogens INTRACELLULARREPLICATION EXTRACELLULARORENDOSOMALREPLICATION 1 ThepathwayofMHCI associatedendogenousAgpresentation endogenousantigen suchasvirusAg tumorAg antigenpeptide 8 13aa Peptide MHC ImoleculecomplextosurfaceofAPCsubmittoCD8 T transportedtoendoplasmicreticulumbyTAP degradedbyproteasome LMP incytoplasm Degradationintheproteasome ThecomponentsoftheproteasomeincludeMECL 1 LMP2 LMP7 ThesecomponentsareinducedbyIFN andreplaceconstitutivecomponentstoconferproteolyticproperties LMP2 7encodedintheMHCProteasomecleavesproteinsafterhydrophobicandbasicaminoacidsandreleasespeptidesintothecytoplasm Cytoplasmiccellularproteins includingnon selfproteinsaredegradedcontinuouslybyamulticatalyticproteaseof28subunits Proteasome theCytosolicMeatGrinderThatChopsUpProteins ENDOPLASMICRETICULUM CYTOSOL PeptideantigensproducedinthecytoplasmarephysicallyseparatedfromnewlyformedMHCclassI LMP TAP Transporter associatedwithantigenprocessing TAP1 2 Transporterhaspreferencefor 8aminoacidpeptideswithhydrophobicCtermini CalnexinbindstonascentclassI chainuntil 2 Mbinds 2 MbindsandstabilisesfloppyMHC Tapasin calreticulin TAP1 2formacomplexwiththefloppyMHC CytoplasmicpeptidesareloadedontotheMHCmoleculeandthestructurebecomescompact MaturationandloadingofMHCclassI 2 ThepathwayofMHCII associatedexogenousAgpresentation ExogenousantigennewlysynthesisedMHCclassIImolecule intheendoplasmicreticulum endosomeIibindsinthegrooveofMHCclassIImoleculelysosomeproteaseMIICphagolysosomeli CLIP proteaseDMDegradeinto13 18aapeptide releasingtheCLIPandallowingotherpeptidetobindAgpeptide MHCclassIImoleculecomplextransporttothesurfaceofAPC recognizedbyCD4 T Phagocytosis pinocytosis FcR phagocytosis Y Pinocytosis Phagocytosis MembraneIgreceptormediateduptake Uptakeofexogenousantigens Complementreceptormediatedphagocytosis Fcreceptormediatedphagocytosis opsonization Proteasesproduce 24aminoacidlongpeptidesfromantigens Exogenouspathway ProteinantigensInendosome CathepsinB DandLproteasesareactivatedbythedecreaseinpH PathwayforPeptide MHC IIFormation fromEndocytosisProteinsintoVesiclestoFormationofPeptidesonMHC II Needtopreventnewlysynthesised unfoldedselfproteinsfrombindingtoimmatureMHC InvariantchainstabilisesMHCclassIIbynon covalentlybindingtotheimmatureMHCclassIImoleculeandforminganonomericcomplex Intheendoplasmicreticulum MHCclassIImaturationandinvariantchain involveintheassemblingandfoldingofMHCclassIImolecule BlockthegrooveofMHCclassIImolecule LeadtheassembledclassIImoleculetoMIIC ThefunctionsofIi CLIP classII associatedinvariantchainpeptide ClassII associatedinvariantchainpeptide CLIP Ii 3complexesdirectedtowardsendosomesbyinvariantchain proteasedegradesInvariantchainCLIPblocksgrooveinMHCmolecule MHCClassIIcontainingvesiclesfusewithantigencontainingvesicles HLA DMcatalysestheremovalofCLIP MIICcompartment HLA DMReplacesCLIPwithapeptideantigenusingacatalyticmechanism i e efficientatsub stoichiometriclevels DiscoveredusingmutantcelllinesthatfailedtopresentantigenHLA DOmayalsoplayaroleinpeptideexchange MIICcompartmentsortspeptide MHCcomplexesforsurfaceexpressionorlysosomaldegradation SurfaceexpressionofMHCclassII peptidecomplexes MHC IIGoesfromGolgi G toMHC IICompartment MIIC WherePeptideLoadingOccurs 3 Cross presentation ClassIMHCmoleculespresentexogenousAgstoCD8 TcellsCross presentationofAgsbyDCplaysanimportantroleinanti viralinfectionandanti tumorimmunity 3 Cross presentation 4 CD1 mediatedantigenpresentingpathway 2 InteractionbetweenAPCandTcell NonspecificbindingofAPCandTcellSpecificbindingofAPCandTcellTCR peptide MHCco receptor MHCco stimulatorymoleculesTcellsynapseorimmunologicalsynapse Ligand receptorpairsinvolvedinTcellactivation MaincostimulatorymoleculesmediatinginteractionsbetweenTcellsandAPCs 3activation proliferationanddifferentiation ThefirstsignalTCR antigenpeptide MHC doublerecognition CD4 MHCIIorCD8 MHCIThesecondsignal co stimulatorysignal Interactionsbetweenco stimulatorymoleculesonAPCandcorrespondingreceptorsonTcellsCD28 CTLA 4 B7 LFA 1 ICAM 1 LFA 2 LFA 3CytokinesinTcellactivationIL 1 2 6 12 ProliferationanddifferentiationofTcells 1 CD4 Tcells Th Tr Treg Th17 Tmregulatedbycytokines2 CD8 Tcells TcTh dependentTh independent virusinfectedDCthathighlyexpressco stimulatorymoleculescandirectlystimulateCD8 Tcells ActivationofCD8 Tcells CytokinesarerequiredinTcellproliferationanddifferentiation ActivatedTcellscanproducecytokines IL 2 4 7 10 etc andexpresscytokinereceptors thatpromoteTcellstoproliferateanddifferentiate 4 EffectorfunctionsofactivatedTcells 1 CD4 TcellsTh1 secreteIFN etc expressCD40LexpressFasL killFas targetcellseffectonlymphocytes IL 2effectonneutrophil TNF Th2 promoteBcellgrowthandIgproductionmediatehypersensitivityTh17 IL 17 Il 8 TNF enhanceleukocyterecruitmentandinflammation Activatemacrophages Twotypesofcell mediatedimmunity Cell mediatedimmunityagainstintracellularmicrobes ActivationofmacrophagesbyTlymphocytes Cytotoxicity killtargetcellsa necrosis perforinandgranzymeb apoptosis granzyme FasLCharacteristicsofCD8 Tcellcytotoxicitya Specificityb MHCIrestrictionc Highefficiency 2 CD8 Tcells Downloadedfrom StudentConsult on1June200603 50PM 2005Elsevier MechanismsofkillingofinfectedcellsbyCD8 CTLs 3 memoryTcells 1 CD45RA CD45RO 2 Long livedmemorytospecificantigen3 Mediatefaster strongerandmoreeffectiveimmuneresponse4 Mechanism lowdependentoncostimulatorymoleculesormoresensitivitytocytokines Activationinducedcelldeath AICD 1 ActivationinducedcelldeathActivatedTcellsexpressFasLthatinduceapoptosisofFaspositiveTcells 2 PassivecellapoptosisAg survivalsignalsandgrowthfactors Activation induceddeathofTcells Bcell mediatedhumoralimmuneresponse Humoralimmunityismediatedbyantibodiesandisthearmoftheadaptiveimmuneresponsethatfunctionstoneutralizeandeliminateextracellularmicrobesandmicrobialtoxins Phasesandtypesofhumoralimmuneresponses 1 PhasesAntigenrecognitionphaseActivation proliferationanddifferentiationphaseEffectorphase2 TypesResponsetoTD AgResponsetoTI Ag Phasesofhumoralimmuneresponses Effectorphase 1 BcellsrecognizeTD Aga BCRdirectlyrecognizesBcellepitopesb Ig Ig transferthefirstsignalc Effectofcoreceptors CD21 CD19 CD81 d Signallingpathways Theroleofcoreceptor CD19 CD21 CD81 inBcellactivation 2 RoleofThcellsinhumoralimmuneresponsetoTD Ag ForaproteinAgtostimulateAbresponse BcellsandThcellsspecificforthatAgmustcometogetherinlymphoidorgansandinteractinawaythatstimulatesBcellproliferationanddifferentiation a ActivationandmigrationofhelperTcells Thcellsthathavebeenactivatedtodifferentiateintoeffectorcellsinteractwithantigen stimulatedBcellsattheedgesoflymphoidfolliclesintheperipherallymphoidorgans TheinteractionsofThcellsandBcellsinlymphoidtissues b PresentationofAgsbyBcellstoThcells BcellsthatbindproteinAgsbytheirBCRendocytosetheseAgs processtheminendosomalvesicles displayMHCII peptidesforrecognitionofThcells BcellsandThcellsrecognizedifferentepitopesofthesameproteinAg AgpresentationbyBcellstoThcells c MechanismsofThcell mediatedactivationofBcells ThcellsthatrecognizeAgpresentedbyBcellsactivatedBcellbyexpressingCD40Landbysecretingcytokines IL 2 IFN IL 4 IL 5 IL 6 IL 13 etc Downloadedfrom StudentConsult on1June200603 50PM 2005Elsevier MechanismsofThcell mediatedactivationofBcells Theanatomyofhumoralimmuneresponses 2 BcellmaturationinGerminalcenter Hypermutation 超突变 AffinityMaturation 亲和力成熟 Receptorediting 受体编辑 ClassSwitch 抗体类别转换 AffinitymaturationinAbresponses Affinitym