HowdoesourbodyHowdoesourbodydefendLecture18-EssentialsofCHAPTER22BROCKBIOLOGYOFSchoolofLifeScienceandBiotechnology,ShanghaiJiaoTongUniversity18.5PresentationofAntigenstoT18.5PresentationofAntigenstoTTcellsinteractspecificallywithantigenthroughthecell-surface(T-cellreceptor).T-cellreceptors(TCRs)interactwithantigensheldinplaceonantigen-presentingcells(抗原提呈細(xì)胞)throughmajorhistocompatibilitycomplex(主要組織相容性復(fù)合體,MHC)proteins.ShanghaiJiaoTongMolecularbasisofspecificTcell?TheMolecularbasisofspecificTcell?TheT-cellreceptorisamembrane-spanningproteinthatextendsfromtheTcellsurfaceintotheextracellularenvironment.AfunctionalTCRconsistsoftwoproteins,anchainandachain.Eachofthesischainshasavariable(V)domainandaconstant(C)domain.TheVandVdomainscooperatetoformacompleteantigen-bindingsite.??ShanghaiJiaoTongStructureStructureoftheT-cellreceptor(TCR).TheVdomainsofthechainandchaincombinetoformthepeptideMajorHistocompatibilityMajorhistocompatibilitycomplex(MHC):MajorHistocompatibilityMajorhistocompatibilitycomplex(MHC):ageneticencodedMHCproteinsinallvertebrates主要組織相容性復(fù)MHCproteinsfunctionasantigen-presentingmoleculesandinteractwithboththeantigenandtheTCR.MHCproteinsarenotstructurallyidenticalwithinaspecies.DifferentindividualsoftenshowsubtledifferencesintheaminoacidsequenceoftheirMHCmolecules.ShanghaiJiaoTongStructuresStructuresofthetwotypesofMHCClassIMHCprotein.The1and2domainsinteracttoformthepeptideantigen-bindingsite.Foundonthesurfacesofallnecleatedcells.ClassIIMHCprotein.The1and1domainscombineformthepeptideantigen-bindingsite.FoundonlyonthesurfaceofBcell,macrophages,andotherantigen-presentingcells(APCs).ClassIantigenpresenting1)ClassIantigenpresenting1)Protein)tid,classI,aretransportedtoeTerac,andgestheclassIaCdtraoacossthote)stenfasefsndcytotoxins,proteinsthatkillthetargetcell.theclassIproteinsaremadeandassembledintheendoplasmicClassIIantigenpresenting1.)classIIClassIIantigenpresenting1.)classIIproteinsare.n3.)TheclassIIproteinfi,i.ircsIItimte),are oecc.rcells.TheTHcellsreleasecytokinesthatactonothercellstoactivateanimmuneresponse.18.6T-cytotoxiccellsandNaturalkiller18.6T-cytotoxiccellsandNaturalkiller細(xì)胞毒T細(xì)胞與自然殺傷細(xì)胞TccellsareinvolvedinthedestructionofcellsdisplayforeignantigensontheirShanghaiJiaoTongTcTccells,areactivatedbyantigenspresentedonanycellinthecontextofMHCITheTccellsreleasegranulesthatcontainperforin穿孔素andgranzymes顆粒酶,cytotoxins細(xì)胞毒素whichperforatethetargetcellandNaturalkillerNKcellsareneitherTNaturalkillerNKcellsareneitherTcellsnorBNKcellsresembleTccellsintheirabilitytokillforeigncells.(e.g.useperforinandgranzymestokilltargets)NKcellsdifferfromTccellsinthattheykilltargetsintheabsenceofrecognitionofaspecificantigen.ThemoleculartargetforNkcellsseemstobethelackofappropriateMHCclassIproteins.ShanghaiJiaoTong18.7T-helpercells:activatingtheimmuneMacrophage18.7T-helpercells:activatingtheimmuneMacrophageMacrophagesbind,process,andpresentantigentoTH1TH1cellsinturncanusecytokinessuchasinterferongammatoactivatemacrophagestokillintracellularModeratedoseofM.TuberculosistoinduceTcellmediatedimmunitytobacterialpathogens??ShanghaiJiaoTongT-inflammatorycells,T-inflammatorycells,orTH1cells,areactivatedbyantigenspresentedonmacrophagesinthecontextofMHCIIprotein.TheTH1cellsrespondbyproducingcytokinesthatstimulatethemacrophagestoincreasephagocyteactivityandpromote TheroleofT TheroleofTcellsinspecific III.Humoral體液免疫Process:Antigen-antibodyIII.Humoral體液免疫Process:Antigen-antibodyAntibodyproductionbyBcellsstimulatedbyTH2ShanghaiJiaoTong18.8AntibodiesProteinmoleculesthatareable18.8AntibodiesProteinmoleculesthatareabletocombinewithantigenicderminants.Fivemajor?????ShanghaiJiaoTongIgGconsistsoftwoheavychainsmolecularweight)andtwolightchains(25,000weight),withatotalmolecularweightof150,000.Oneheavyandonelightchaininteracttoformanantigen-bindingunitImmunoglobulinGThemostabundantimmunoglobulin,80%Twoantigenbindingdomains,ImmunoglobulinGThemostabundantimmunoglobulin,80%Twoantigenbindingdomains,bivalentLightchain-onevariabledomain,oneconstantHeavychain-onevariabledomain,threecontantShanghaiJiaoTongImmunoglobulinGShanghaiJiaoTongImmunoglobulinGShanghaiJiaoTong(a)IgG,andIgDhavethree(a)IgG,andIgDhavethreeconstantclasses.AllclassesofimmunoglobulinshaveVHandVLdomains(red)thatbindantigen(b)IgMandIgEeachhaveafourthM(IgM)isfoundinserumasaM(IgM)isfoundinserumasaconsistingoffiveIgMproteinslinkedtooneanotherviadisulfidebondsandaJchainSecretoryimmunoglobulinA(sIgA)isoftenfoundinbodysecretionsasaSecretoryimmunoglobulinA(sIgA)isoftenfoundinbodysecretionsasadimerconsistingoftwoIgAproteinscovalentlylinkedtooneanotherviaaJchainprotein.18.9AntibodyTcell-Bcellinteraction:18.9AntibodyTcell-Bcellinteraction:TheproductionofimmunoglobulinsinresponsetoantigeninvolvesinteractionsbetweenTcellsandBcellsthroughtheirrespectiveantigen-specificcellsurfaceShanghaiJiaoTongBcellfunctionsasancell(APC)andconcentratesantigenusinganigen-specificBcellfunctionsasancell(APC)andconcentratesantigenusinganigen-specificreceptors.Afterprocessing,antigenispresentedtotheTH2cellbyaclassIIMHCmolecule.TheTH2cellthensignalsthesameBcelltoproliferateandformplasmaormemorycells.Aftersubsequentantigenexposure,memorycellsquicklyconverttoplasmaTcell–BcellinteractionandantibodyThesecondaryresponse,alsocalledaboosterresponse,maybemorethantenfoldgreaterthantheprimaryresponseThesecondaryresponse,alsocalledaboosterresponse,maybemorethantenfoldgreaterthantheprimaryresponse.NotetheclassswitchfromIgMproductionintheresponsetoIgGproductioninthe18.10ComplementFunctions補(bǔ)體功Complementisaseriesofproteinsthatareactivated18.10ComplementFunctions補(bǔ)體功Complementisaseriesofproteinsthatareactivatedbyinteractionswithantigen-antibodyComplementcatalyzesthebactericidalandlyticactionsofantibodiesagainstmanygram-negativebacteria.ActivationofcomplementoccursonlywithantibodiesoftheIgGandIgMShanghaiJiaoTongComplementactivation補(bǔ)Complementactivation補(bǔ)體活Thesequence,ofthevariouscomponentsastheyinteracttolyseacell.Panel1:BindingoftheantibodyrecognitionunitC1qandotherC1panel2:theC4-C2panel3:theC4-C2-C3-C5complex—afteractivation,theC5unittravelstoanadjacentmembranesite;panel4,bindingofC6,C7,C8,andC9,resultinginmembraneLysisbyThree-dimensionalLysisbyThree-dimensionalviewoftheholeformedbycomplementcomponentsC5throughC9.ImportantquestionsontheimmuneImportantquestionsontheimmuneHowcanaTcelltellselffromnonselfHowcantheBcellsproducesomanydifferentkindsofantibodies?Whatcanwedowithourunderstandingonmolecularandcellularmechanismsofimmunereactionsinourbody?ShanghaiJiaoTongQuestion1:HowcanQuestion1:HowcanTcellstellselffromnon-self?HowcantheTcellstellselfHowcantheTcellstellselffromnon-selfantigens?(ImmuneTolerance)MHCProteinsserveasmolecularreferencepointsthatpermitTcellstoidentifyforeignantigensMHCmoleculesactasaplatformonwhichtheforeignantigenisboundTCRscanbindMHCandrecognizeforeignantigensembeddedintheMHCstructureShanghaiJiaoTongT-cellSelectionandTcellsundergoT-cellSelectionandTcellsundergoselectionforantigen-reactiveTcellsandselectionagainstclonesthatreactwithselfShanghaiJiaoTongT-cellselectionandclonaldeletion.TcellsundergoT-cellselectionandclonaldeletion.TcellsundergoastepwiseselectionprocessinthethymusQuestion2:HowcantheBcellsproducesomanyQuestion2:HowcantheBcellsproducesomanydifferentkindsofantibodies?ClonalselectionisahypothesisstatingClonalselectionisahypothesisstatingthatantigen-reactiveBcellorTcellhasacell-surfacereceptorforasingleantigen.ShanghaiJiaoTongIndividualBcells,specificforasingleantigen,proliferateandexpandtoformacloneafterinteractionwithIndividualBcells,specificforasingleantigen,proliferateandexpandtoformacloneafterinteractionwiththespecificantigen.Thespecificantigenactsastheselectionagent,drivingselectionandthenproliferationoftheindividualantigen-specificBcell.ClonalcopiesClonalcopiesoftheallhavethesamesurfacereceptor.ContinuedexposuretoantigenresultsincontinuedexpansionofthecloneDetailedDetailedstructureofGenerearrangement:“genesinhypothesis基因Generearrangement:“genesinhypothesis基因重Asinglelightorheavychainisactuallyencodedseveralgenes.GenesforV,D,J,andCregionswereseparatedfromaoneanotherinthegenome.??150Vgenes,5Jgenes,5Cgenesforlight200Vgenes,50Dgenes,4Jgenes,2CgeneforheavyShanghaiJiaoTongFormationFormationofactivegeneforheavychainviasomaticFormationFormationofactivegeneforlightchainviasomaticSomaticPossibleantibody??Lightchain-750kinds;HeavySomaticPossibleantibody??Lightchain-750kinds;Heavychain-4000thecombination-3,000,000ImprecisioninthejoiningatVDJDregioninheavychaincanbereadinthreereadingHypermutation:themutationofIggenesisathigherratesthanthemutationratesobservedinothergenes.Thenumberofpossibleantibody-ShanghaiJiaoTongLearningLearningtobemoreWhatcanwedowithourunderstandingonthemolecularandcellularmechanismsofWhatcanwedowithourunderstandingonthemolecularandcellularmechanismsofimmunereactionsinourAntibodypreparationwhichcanonlyAntibodypreparationwhichcanonlyreactwithoneProducingonekindofantibodyusinganimpureHighspecificityandreproducibilityinShanghaiJiaoTongEachantigen-activatedB