免疫细胞和免疫应答

免疫细胞和免疫应答第一页，共161页。Cellsofimmunesystem第二页，共161页。Tlymphocytes第三页，共161页。ⅠDevelopmentofTcells第四页，共161页。StagesofTcellmaturation第五页，共161页。PositiveandnegativeselectionPositiveselection（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）第六页，共161页。第七页，共161页。Tcellsurfacemarkers

第八页，共161页。TCR-CD3complexTCRAheterodimercomprisinganandachainoraandachainjoinedbyadisulfidebond.Function:specificrecognitionofpeptide-MHCcomplex.第九页，共161页。TCR-CD3complex第十页，共161页。Consistsof5proteinsthataredesignatedas,,,and

.Threedimers:,,()ThecytoplasmicdomaincontainsITAM(immunoreceptortyrosine-basedactivationmotif)YXXL/VFunction:transductionofsignalsthatleadtoTcellactivation.CD3第十一页，共161页。

Mainco-stimulatorymoleculesmediatinginteractionsbetweenTcellsandAPCs第十二页，共161页。Receptorsofmitogens(丝裂原受体)PHA-RConA-RPWM-RCytokinereceptor(细胞因子受体)Virusreceptor(病毒受体)第十三页，共161页。Leukocytedifferentiationantigen(LDA，白细胞分化抗原):Thecellsurfacemarkerswhichexpressordisappearonthedifferentleukocytesinthedifferentstageofdifferentiationandactivation.第十四页，共161页。TCellSurfaceMoleculesCD(clusterofdifferentiation，分化群):Cellsurfacemoleculesofleucocytesthataredistinguishablewithmonoclonalantibodiesasanimmunologicmarker.CD1-350第十五页，共161页。CD4andCD8(coreceptor)Function:1)HelptheinteractionbetweenTcellandAPCandenhancetherecognitionofantigenbyTCR;2)helptheTCR-CD3signalstransductionCD4:MHCIIAgbinding,ReceptorofHIVgp120CD8:MHCIAgbinding第十六页，共161页。Co-stimulatorymoleculesCD28:itsligandsareB7familymolecules,includingB7-1/2(CD80/CD86)

Function:costimulation,activationofTcellsCTLA-4(CD152):homodimer,homologoustoCD28.

Function:inhibitsTcellcostimulation(thecytoplasmicdomaincontainsITIM)

第十七页，共161页。©2005Elsevier第十八页，共161页。Celladhesionmolecules

(细胞粘附分子)CAM:Agroupofproteinsinvolvedinadhesionofcelltocellorcelltoextra-cellularmatrix(ECM),suchasICAM-1,ICAM-2,ICAM-3,VCAM-1andPECAMetc.第十九页，共161页。CategoriesofCAM1.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

第二十页，共161页。III.Tcellsubsets1．TCRTcellsandTCRTcells2．CD4+TandCD8+Tcells3．Th,TcandTreg4.NaiveTcells（初始型）,effectorTcells（效应性）andmemoryTcells（记忆性）第二十一页，共161页。第二十二页，共161页。IV.FunctionsofTcells1.

CD4+helperTcells(Th)Th0:Thcellsthatsecretebroadspectrumofcytokinesatlowlevel.Th1:produceIL-2andIFN-,butnotIL-4.Theyarechieflyresponsibleforcell-mediatedimmuneresponses,butcanalsohelpBcellstoproduceIgG2a,butnotmuchIgG1orIgE;Th2:secreteIL-4,5,10,13,butnotIL-2andIFN-,areveryefficienthelpercellsforproductionofantibody,especiallyofIgG1andIgE;第二十三页，共161页。第二十四页，共161页。第二十五页，共161页。IV.FunctionsofTcells1.

CD4+helperTcells(Th)Th3:produceTGF-β.inhibitTh1mediatedimmunityandinflamationinhibitfunctionofB,Tc,NKTh17:secreteIL-17.innateimmunityandinflammation第二十六页，共161页。2.

CD8+cytotoxicTcells(CTL,Tc)Function:directlykilltargetcells(cytotoxicity)Mechanisms:

第二十七页，共161页。3.

CD4+CD25+regulatoryTcells(Tr)Foxp3positive

Function:

Down-regulationofimmuneresponsebyinhibitingtheactivationandproliferationofCD4+orCD8+Tcells.

Mechanisms:Directinhibitionbycontactingtargetcells.Inhibitorycytokines:IL-10,TGF-,etal.

第二十八页，共161页。©2005Elsevier第二十九页，共161页。Bcell

第三十页，共161页。I.DevelopmentofBcellBlymphocytesrefertoBonemarrow-derivedlymphocytesorBursa-derivedlymphocytesAbout20％ofthecirculatinglymphoidpoolareBcells.第三十一页，共161页。DevelopmentofBcellinBM第三十二页，共161页。Ⅱ.B-cellsurfacemarkers第三十三页，共161页。1.BCRcomplexBCR(mIg)：VH,VL----Ag

matureBcells:mIgMandmIgD.

Function:specificallyrecognizesantigen.

Ig/Ig(CD79a/CD79b):heterodimercytoplasmicdomainscontainITAM.

Function:1.transfersthesignalsthatleadtoBcellactivation.

2.

transportstheIg第三十四页，共161页。2.Co-receptors:CD19/CD21/CD81complex第三十五页，共161页。3.Co-stimulatorymolecules(1)CD40(2)CD80/CD86(3)ICAM-1,LFA-1第三十六页，共161页。4.OtherreceptorsCD20:BcellmarkerCD22:inhibitoryreceptorCD32:FcRⅡ第三十七页，共161页。第三十八页，共161页。

B-cellsubsetsB1cells(CD5+):ManyofthefirstBcellsthatappearduringontogenyexpressCD5,amarkeroriginallyfoundonTcells.(expressmIgM,nomIgD).TheyrespondwelltoTI-AgandmayalsobeinvolvedintheAgprocessingandpresentationtoTcells.

Functions

1.produceanti-bacterialIgMthefirstlineofdefenceagainstmicroorganisms;2.producepolyreactiveAbclearanceofdenaturedselfcomponents;3.produceauto-Ab,therebyparticipatinginthepathogenesisofsomeautoimmunediseases.

第三十九页，共161页。B2cell:CD5-Bcells.mIg:IgM,IgDafterantigenicstimulation,inthepresenceofTh,theyproducemoreIgGthanIgM第四十页，共161页。B1andB2cellB1B2CD5+-renewingSelfrenewingDerivedfromBMSpontaneouslyIgproductionHighLowAntigenCarbohydrateProteinClassofIgIgM>IgGIgG>IgMSpecificityMulti-specificityMono-specificitySomaticHypermutationLow/noHighmemory-+第四十一页，共161页。NKCells

第四十二页，共161页。NKcellsweredefinedinitiallybytheirabilitytolysecertaintumorcelllinesandvirallyinfectedcellswithoutpriorimmunization,andsomediateaformofinnate(ornatural)immunitythatistermed“naturalkilling”.第四十三页，共161页。I.OntogenyanddistributionofNKcellDerivefromabonemarrowprecursorlargegranularlymphocytesdistribution:peripheralblood,spleenNKcellsarerareinlymphnodeanddonotcirculatethroughthelymph.

第四十四页，共161页。II.Surfacemarkers1.CD562.CD16(FcRIII):ADCC3.CD24.CD11a/CD18(LFA-1)TheyneverthelessservetoidentifyNKcells,whicharegenerallyCD16+,CD56+,CD3-,whereasTcellsareCD16-,CD56-,CD3+.第四十五页，共161页。5.NKcellsreceptorsKAR(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第四十六页，共161页。Downloadedfrom:StudentConsult(on1June200601:58PM)©2005Elsevier第四十七页，共161页。III.FunctionsofNKcells1.Anti-infection

provideanearlyinnatebarriertoinfectionbyeliminatinginfectedhostcell2.Anti-tumor

killtumorcellsdirectly:perforin,granularenzyme

ADCC3.Immunoregulation

producecytokinessuchasIFN-,TNF-,G-CSF第四十八页，共161页。Antigen-presentingcells抗原提呈细胞第四十九页，共161页。ProfessionalAPCs:Dendriticcells;Monocytes/macrophagesandBcellsClassificationofAPCs第五十页，共161页。

ClassificationofAPCs

Non-professionalAPCEndothelialcell(EC)FibroblasticcellActivatedTcellInducibleexpressionofMHCclassIImoleculesTargetcells

ExpressionofMHCclassImolecules第五十一页，共161页。BonemarrowBloodTissueHSCMyeloidprogenitorPre-monocyteMonocyteMonocyteMacrophageIIMonocytesandmacrophages

1.Differentiationanddistribution第五十二页，共161页。

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第五十三页，共161页。3.BiologicalfunctionsofM(1)Phagocytosisandcytotoxicactivity:

chemotaxis:blood----tissueopsonization:Ig,C3b,C4banumberofantimicrobialandcytotoxicsubstancesproducedbyactivatedMcandestroyphagocytosedmicroorganisms.

Reactiveoxygenintermediates,NO,proteinases.第五十四页，共161页。phagocytosis第五十五页，共161页。(2)Antigenprocessingandpresentation:phagocytosispinocytosisreceptor-mediatedendocytosis第五十六页，共161页。(3)Secretionofsolublefactorstoregulateimmuneresponseenzymes:lysozyme,myeloperoxidase,etc.cytokines:IL-1,IL-6,TNF,IL-12,IL-18,plement:C1~C9,Bfcoagulationfactor,PG,LTs,ACTH,etc.第五十七页，共161页。Dendriticcells

(DCs，树突状细胞)第五十八页，共161页。1.Surfacemarkers(1)MHCclassIImolecule(2)Specificmarks:CD1a,CD11c,CD83(human);33D1,NLDC145(mouse)(3)Co-stimulatorymolecules:CD80,CD86,CD40,CD44,CD54,integrinβ1,β2(4)Receptor:FcR,TLR,第五十九页，共161页。GM-CSFTNF-aIL-42.ClassificationofDC:originofDCHSCMyeloidprogenitorLymphoidprogenitorMyeloidDCMomacrophageMyeloid

DC

PMNLymphoid

DC第六十页，共161页。2.ClassificationofDC:第六十一页，共161页。DendriticCellMaturation第六十二页，共161页。MigratingDC第六十三页，共161页。2.ClassificationofDC:distributionLymphoidtissueDC

follicularDC(FDC),interdigitatingDC(IDC),thymicDCNon-lymphoidtissueDCLangerhanscell,interstitialDCCirculatingDCperipheralbloodDC,veiledcell第六十四页，共161页。4.FunctionofDCAntigenpresentingandactivationofadaptiveTcellsImmunoregulationMaintainanceandinductionofimmunetolerance第六十五页，共161页。Bcells第六十六页，共161页。第六十七页，共161页。ImmuneResponse免疫应答第六十八页，共161页。ImmuneResponse（免疫应答）

innateimmuneresponse(固有免疫应答)

naturalimmuneresponse

non-specificimmuneresponse

adaptiveimmune

response（适应性免疫应答）

acquiredimmuneresponse

specificimmuneresponse第六十九页，共161页。Innateandadaptiveimmunity第七十页，共161页。innateimmuneresponse

Physiologicalbarriersskinmucousmembranes

Phagocytosispolymorphonuclearleukocytes(PMN)macrophagesToll-likereceptor4/LPS

Naturalkiller(NK)cell

Complement,Acutephaseproteins

第七十一页，共161页。innateimmuneresponse第七十二页，共161页。innateimmuneresponse(Lung)MacrophageAttackingE.coli

第七十三页，共161页。Adaptiveimmuneresponse第七十四页，共161页。ImmuneResponse第七十五页，共161页。FeaturesofInnateandAdaptiveImmunity第七十六页，共161页。Tcell-mediatedimmuneresponse

第七十七页，共161页。TypesofintracellularmicrobescombatedbyTcell-mediatedimmunity第七十八页，共161页。PhasesofTcellresponsesThreephasesAntigenrecognitionphaseActivation,proliferationanddifferentiationphaseEffectorphase第七十九页，共161页。第八十页，共161页。第八十一页，共161页。Ⅰ.Antigenrecognition

1AgpresentationbyAPC第八十二页，共161页。Antigenprocessingandpresentation第八十三页，共161页。I.Uptakeofantigens第八十四页，共161页。YThesiteofpathogenreplicationormechanismofantigenuptakedeterminestheantigenprocessingpathwayusedYCytosoliccompartmentEndogenousprocessing(Viralantigens)VesicularCompartmentContiguouswithextracellularfluidExogenousprocessing(Streptococcal,Mycobacterialantigens)DistinctmechanismsofantigengenerationareusedtoraiseTcellssuitedtotheeliminationofendogenousorexogenouspathogensINTRACELLULARREPLICATIONEXTRACELLULARORENDOSOMALREPLICATION第八十五页，共161页。第八十六页，共161页。1.ThepathwayofMHCI-associatedendogenousAgpresentation

endogenousantigen(suchasvirusAg,tumorAg)

antigenpeptide（8-13aa）

Peptide/MHC-Imoleculecomplex

tosurfaceofAPCsubmittoCD8+TtransportedtoendoplasmicreticulumbyTAPdegradedbyproteasome(LMP)incytoplasm第八十七页，共161页。DegradationintheproteasomeThecomponentsoftheproteasomeincludeMECL-1,LMP2,LMP7.ThesecomponentsareinducedbyIFN-andreplaceconstitutivecomponentstoconferproteolyticproperties.LMP2&7encodedintheMHCProteasomecleavesproteinsafterhydrophobicandbasicaminoacidsandreleasespeptidesintothecytoplasmCytoplasmiccellularproteins,includingnon-selfproteinsaredegradedcontinuouslybyamulticatalyticproteaseof28subunits第八十八页，共161页。Proteasome,theCytosolicMeatGrinderThatChopsUpProteins第八十九页，共161页。ENDOPLASMICRETICULUMCYTOSOLPeptideantigensproducedinthecytoplasmarephysicallyseparatedfromnewlyformedMHCclassINewlysynthesisedMHCclassImoleculesPeptidesneedaccesstotheERinordertobeloadedontoMHCclassImoleculesLMPTAP第九十页，共161页。ERmembraneLumenofERCytosolTransporter-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)domainHydrophobictransmembranedomainPeptideantigensfromproteasome第九十一页，共161页。EndoplasmicreticulumCalnexinbindstonascentclassIchainuntil2-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&2formacomplexwiththefloppyMHCCytoplasmicpeptidesareloadedontotheMHCmoleculeandthestructurebecomescompactMaturationandloadingofMHCclassI第九十二页，共161页。第九十三页，共161页。2.ThepathwayofMHCII-associatedexogenousAgpresentationExogenousantigennewlysynthesisedMHCclassIImolecule

(intheendoplasmicreticulum)endosomeIibindsinthegrooveofMHCclassIImolecule

lysosomeproteaseMIICphagolysosomeli(CLIP)proteaseDMDegradeinto1318aapeptide+releasingtheCLIPandallowingotherpeptidetobind

Agpeptide/MHCclassIImoleculecomplextransporttothesurfaceofAPC,recognizedbyCD4+TPhagocytosis,pinocytosis,FcR-phagocytosis第九十四页，共161页。YYPinocytosisPhagocytosisMembraneIgreceptormediateduptakeYUptakeofexogenousantigensComplementreceptormediatedphagocytosisYFcreceptormediatedphagocytosisopsonization第九十五页，共161页。Proteasesproduce~24aminoacidlongpeptidesfromantigensEndosomesExogenouspathwayIncreaseinacidityCellsurfaceTolysosomesUptakeProteinantigensInendosomeCathepsinB,DandLproteasesareactivatedbythedecreaseinpH第九十六页，共161页。PathwayforPeptide+MHC-IIFormation,fromEndocytosisProteinsintoVesiclestoFormationofPeptidesonMHC-II第九十七页，共161页。Needtopreventnewlysynthesised,unfoldedselfproteinsfrombindingtoimmatureMHCInvariantchainstabilisesMHCclassIIbynon-covalentlybindingtotheimmatureMHCclassIImoleculeandforminganonomericcomplexIntheendoplasmicreticulumMHCclassIImaturationandinvariantchain第九十八页，共161页。involveintheassemblingandfoldingofMHCclassIImolecule;BlockthegrooveofMHCclassIImolecule;LeadtheassembledclassIImoleculetoMIIC.ThefunctionsofIi:CLIP：classII-associatedinvariantchainpeptide第九十九页，共161页。EndosomesCellsurfaceUptakeClassII-associatedinvariantchainpeptide(CLIP)(-Ii)3complexesdirectedtowardsendosomesbyinvariantchainproteasedegradesInvariantchainCLIPblocksgrooveinMHCmoleculeMHCClassIIcontainingvesiclesfusewithantigencontainingvesicles第一百页，共161页。HLA-DMcatalysestheremovalofCLIPMIICcompartmentHLA-DMReplacesCLIPwithapeptideantigenusingacatalyticmechanism(i.e.efficientatsub-stoichiometriclevels)DiscoveredusingmutantcelllinesthatfailedtopresentantigenHLA-DOmayalsoplayaroleinpeptideexchangeSequenceincytoplasmictailretainsHLA-DMinendosomesHLA-DMHLA-DR第一百零一页，共161页。MIICcompartmentsortspeptide-MHCcomplexesforsurfaceexpressionorlysosomaldegradationSurfaceexpressionofMHCclassII-peptidecomplexesExportedtothecellsurface(t1/2=50hr)Senttolysosomesfordegradation第一百零二页，共161页。MHC-IIGoesfromGolgi(G)toMHC-IICompartment(MIIC)WherePeptideLoadingOccurs第一百零三页，共161页。第一百零四页，共161页。第一百零五页，共161页。第一百零六页，共161页。3.Cross-presentationClassIMHCmoleculespresentexogenousAgstoCD8+TcellsCross-presentationofAgsbyDCplaysanimportantroleinanti-viralinfectionandanti-tumorimmunity.第一百零七页，共161页。3.Cross-presentation第一百零八页，共161页。4,CD1-mediatedantigenpresentingpathway第一百零九页，共161页。第一百一十页，共161页。2,Interactionbetween

APCandTcellNonspecificbindingofAPCandTcellSpecificbindingofAPCandTcellTCR-peptide-MHCco-receptor-MHCco-stimulatorymoleculesTcellsynapseorimmunologicalsynapse

第一百一十一页，共161页。Ligand-receptorpairsinvolvedinTcellactivation第一百一十二页，共161页。

MaincostimulatorymoleculesmediatinginteractionsbetweenTcellsandAPCs第一百一十三页，共161页。3activation,proliferationanddifferentiation

Thefirstsignal

TCR-antigenpeptide-MHC(doublerecognition)CD4-MHCIIorCD8-MHCIThesecondsignal(co-stimulatorysignal)Interactionsbetweenco-stimulatorymoleculesonAPCandcorrespondingreceptorsonTcells

CD28/CTLA-4—B7,LFA-1—ICAM-1,LFA-2—LFA-3

CytokinesinTcellactivation

IL-1,2,6,12

第一百一十四页，共161页。第一百一十五页，共161页。ProliferationanddifferentiationofTcells1)CD4+Tcells:Th,Tr,Treg,Th17,Tmregulatedbycytokines2)CD8+Tcells:Tc

Th-dependent

Th-independent:virusinfectedDCthathighlyexpressco-stimulatorymoleculescandirectlystimulateCD8+Tcells.

第一百一十六页，共161页。ActivationofCD8+Tcells第一百一十七页，共161页。

CytokinesarerequiredinTcell

proliferationanddifferentiation

ActivatedTcellscanproducecytokines

(IL-2,

4,

7,

10,

etc.)andexpresscytokinereceptors,thatpromoteTcellstoproliferateanddifferentiate.第一百一十八页，共161页。4.EffectorfunctionsofactivatedTcells1)

CD4+Tcells

Th1:secreteIFN-,etc.expressCD40LexpressFasL,killFas+targetcellseffectonlymphocytes:IL-2effectonneutrophil:TNF-,

Th2:promoteBcellgrowthandIgproductionmediatehypersensitivityTh17:IL-17,Il-8,TNF-:enhanceleukocyterecruitmentandinflammation

Activatemacrophages第一百一十九页，共161页。Twotypesofcell-mediatedimmunity第一百二十页，共161页。Cell-mediatedimmunityagainstintracellularmicrobes第一百二十一页，共161页。ActivationofmacrophagesbyTlymphocytes第一百二十二页，共161页。Cytotoxicity:killtargetcellsa.necrosis:perforinandgranzymeb.apoptosis:granzyme,FasLCharacteristicsofCD8+Tcellcytotoxicitya.

Specificityb.MHCIrestrictionc.Highefficiency2)CD8+Tcells第一百二十三页，共161页。Downloadedfrom:StudentConsult(on1June200603:50PM)©2005ElsevierMechanismsofkillingofinfectedcellsbyCD8+CTLs第一百二十四页，共161页。第一百二十五页，共161页。3)memoryTcells1)CD45RA-CD45RO+,2)Long-livedmemorytospecificantigen3)Mediatefaster,strongerandmoreeffectiveimmuneresponse4)Mechanism:lowdependentoncostimulatorymoleculesormoresensitivitytocytokines第一百二十六页，共161页。Activationinducedcelldeath,AICD1)Activationinducedcelldeath

ActivatedTcellsexpressFasLthatinduceapoptosisofFaspositiveTcells.2)PassivecellapoptosisAg,survivalsignalsandgrowthfactors第一百二十七页，共161页。Activation-induceddeathofTcells第一百二十八页，共161页。Bcell-mediatedhumoral

immuneresponseHumoralimmunityismediatedbyantibodiesandisthearmoftheadaptiveimmuneresponsethatfunctionstoneutralizeandeliminateextracellularmicrobesandmicrobialtoxins.第一百二十九页，共161页。

Phasesandtypesofhumoral

immuneresponses

1)PhasesAntigenrecognitionphaseActivation,proliferationanddifferentiationphaseEffectorphase2)TypesResponsetoTD-AgResponsetoTI-Ag第一百三十页，共161页。PhasesofhumoralimmuneresponsesEffectorphase第一百三十一页，共161页。1)BcellsrecognizeTD-Aga.BCRdirectlyrecognizesBcellepitopesb.Ig/Igtransferthefirstsignalc.Effectofcoreceptors(CD21/CD19/CD81)d.Signallingpathways第一百三十二页，共161页。Theroleofcoreceptor(CD19/CD21/CD81)inBcellactivation第一百三十三页，共161页。2)RoleofThcellsinhumoral

immuneresponsetoTD-AgForaproteinAgtostimulateAbresponse,BcellsandThcellsspecificforthatAgmustcometogetherinlymphoidorgansandinteractinawaythatstimulatesBcellproliferationanddifferentiation.第一百三十四页，共161页。a.ActivationandmigrationofhelperTcellsThcellsthathavebeenactivatedtodifferentiateintoeffectorcellsinteractwithantigen-stimulatedBcellsattheedgesoflymphoidfolliclesintheperipherallymphoidorgans.第一百三十五页，共161页。TheinteractionsofThcellsandBcellsinlymphoidtissues.第一百三十六页，共161页。b.PresentationofAgsbyBcellstoThcellsBcellsthatbindproteinAgsbytheirBCRendocytosetheseAgs,processtheminendosomalvesicles,displayMHCII-peptidesforrecognitionofThcells.BcellsandThcellsrecognizedifferentepitopesofthesameproteinAg.第一百三十七页，共161页。AgpresentationbyBcellstoThcells第一百三十八页，共161页。第一百三十九页，共161页。c.MechanismsofThcell-mediated

activationofBcellsThcellsthatrecognizeAgpresentedbyBcellsactivatedBcellbyexpressingCD40Landbysecretingcytokines(IL-2,IFN-,IL-4,IL-5,IL-6,IL-13,etc.).第一百四十页，共161页。Downloadedfrom:StudentConsult(on1June200603:50PM)©2005ElsevierMechanismsofThcell-mediatedactivationofBcells第一百四十一页，共161页。Theanatomyofhumoralimmuneresponses第一百四十二页，共161页。

2)BcellmaturationinGerminalcenter

Hypermutation（超突变

）AffinityMaturation