细胞介导的免疫.ppt

,Cell-MediatedImmunity,AnadaptiveimmuneresponsemediatedbyspecificcellsoftheimmunesystemPrimarilyTlymphocytes(Tcells),butalsomacrophagesandNKcells.Formallydefinedasimmunitythatcanbetransferredfromoneorganismtoanotherbylymphoidcells,butnotbyserumantibody.Tcellsarethemainagentsofcellularimmunity,Tcells,MaincoordinatorsandeffectorsofcellularimmunityDefinedbytheirdevelopmentinthethymusandthepresenceofaT-cellreceptor(TCR)complex,ACD8+cytotoxicTcellkillingatumorcell,Tcells,continued,Twomaintypes:1.CD4+:Stimulateotherimmunecells.2.CD8+CytotoxicTcells:Killintracellularly-infectedcells.TwomajortypesofCD4+Tcells:1.TH1:InflammatoryTcells-Stimulatemacrophagesandpromoteinflammatoryresponses.2.TH2:HelperTcells-StimulateB-cellstoproduceantibodies.(Athirdtype,TH3,hasrecentlybeenshowntopromoteIgAproduction.),Tcelldevelopment,(SeeFigure13-1),Tcelldevelopmentinthethymus:,Cortex,Medulla,Immaturedouble-negativeTcells(CD8-,CD4-),Immaturedouble-positiveTcells(CD8+,CD4+),Positiveselection/negativeselection,CD8+Tcells,CD4+Tcells,MatureTcells,TheTcellReceptor,SimilarinstructuretoImmunoglobulins(similartoasingleFabfragment.Composedoftwoglycoproteinchains(/or/).MostmatureTcellshaveTCRscomposedofanchainandachain(theyarecalled/Tcells).Eachchainhasaconstantregionandavariableregion,similartoanantibodylightchain.ATCRrecognizesasmall(8-13aa)peptideepitopedisplayedonMHC,TCRcomparedtoImmunoglobulins,SimilaritiesBothhavespecificAntigen-bindingregioncreatedbythevariableregionsoftwopolypeptidechains.BothdisplaygreatpotentialfordiversityviageneticrecombinationatthegenomelevelDifferencesATCRismonovalent(hasonebindingsite).AnIgisbivalent(hastwobindingsites).TheTCRhasnosecretedform.Itisalwaysmembrane-bound.TheTCRdoesnotrecognizefreeantigen.AntigenmustbepresentedtoaTcellonanMHCmolecule(nextweek).ThereisnoclassswitchingfortheTCR.Oncemade,theTCRdoesnotchange.,chain,chain,Epitope-bindingsite,Variableregion,Constantregion,Transmembraneregion,TcellReceptor,Immunoglobulin,TheTCRonlyrecognizesspecificpeptide/MHCcomplexesexpressedonthesurfacesofcellsATCRcomplexiscomposedofoneheterodimericTCR(ususally/),plusa5-polypeptideCD3complexwhichisinvolvedincellsignallingforTcellactivation.EachTCRisproducedthroughgeneticrecombinationandrecognizesonesmallpeptideepitope(about8-13aminoacids).OneTcellexpressesonlyonespecifictypeofTCR.,TheTcellReceptor,cont.,CD3istheactivationcomplexfortheTCR,Bindingofantigen/MHCtotheTCRstimulatesCD3.CD3thensendsanactivationsignaltotheinsideoftheTcell.,TCRgenetics:SimilartoIggenetics,(numbersofsegmentsinbookisoff,justlikeforIggenes),Seefigure13-4inbook-thenumbersofsegmentsdiffer,buttheorganizationisthesame,chain,chain,Responsestoinfection-Tcellcomponent,Infection,Infection,Infection,Infection,Infection,Innateimmunity(0-4hours),Earlyinducedresponse(4-96hours),Lateadaptiveresponse96hours),Protectiveimmunity,Immunologicalmemory,Recognitionbypre-formed,non-specificeffectors,Recruitmentofeffectorcells,Transportofantigentolymphoidorgans,Recognitionbypre-formed,AbandTcells,RecognitionbymemoryBcellsandTcells,Removalofinfectiousagent,Removalofinfectiousagent,Removalofinfectiousagent,Removalofinfectiousagent,Removalofinfectiousagent,Recognitionandactivationofeffectorcells,RecognitionbynaveBandTcells,Clonalexpansionanddifferentiationtoeffectorcells,Rapidexpansionanddifferentiationtoeffectorcells,(chapter14)Thischartisnotintendedtobememorized,Theadaptiveimmuneresponseinvolvingantigen-specificTcellsandBcellsisonlyonepartoftheimmuneresponseandisrequiredtoprotectagainstpathogens.Apathogenisbydefinitionanorganismthatcancausedisease.Inotherwords,apathogenisanorganismthatcanbypassinnateimmunityandrequiresanadaptiveimmuneresponseforclearance.,Generationofanadaptiveimmuneresponse,Duringanadaptiveimmuneresponse,Tcellswhichrecognizespecificantigen(s)areselectedfordifferentiationintoarmedeffectorcellswhichundergoclonalexpansiontoproduceabatteryofantigen-specificcells.Clonalexpansionreferstotheprocessbywhichantigen-specificTcellsorBcellsarestimulatedtoreproduceclonesofthemselvestoincreasethesystemsrepertoireofantigen-specificeffectors.Activationofantigen-specificTcells(theinitiationoftheadaptiveresponse)occursinthesecondarylymphtissues(lymphnodesandspleen).Thisactivationdependsuponantigenpresentationbyaprofessionalantigenpresentingcell(APC)alongwithsimultaneousco-stimulation.(eg.,B7ontheAPC,CD28ontheTcell).,Initiationoftheadaptiveimmuneresponse,Thefirststepisthedrainingofantigenintothelymphnode(s).Inthelymphnode(s)(orspleen),antigensaretrappedbyprofessionalAPCswhichdisplaythemtoTcells.,TheprofessionalAntigenPresentingCells(APCs),ThreetypesofAPCarefoundinthelymphnodes:Dendriticcells-constitutivelyexpressMHCIandMHCII(canstimulatebothCD4+andCD8+Tcells)aswellasB7(theco-stimulatorysignal).Antigenpresentationappearstobethesolepurposeofdendriticcells,andthesecellscanbeinfectedbyawidevarietyofviruses.Dendriticcellsarenotphagocytic.TheycanpresentsomeviralpeptidesontheirMHCII,andcontributetotheinductionofantibodyagainstviruses.Theyareveryefficientatstimulationofcytotoxicresponses.Macrophages-RestingmacrophagesexpresslittleMHCIIorB7,buthavereceptorsforbacterialcellwallcomponentswhich,uponbinding,activatethemacrophagetoexpresshighlevelsofB7andMHCII.Onceactivated,macrophagesareefficientatstimulatingCD4+Tcells,bothforinflammatoryresponsesandhelper(antibody)responses.Bcells-BcellsexpresshighlevelsofMHCII,butnotB7.MicrobialcellwallcomponentscaninduceB7expressionbyBcells(likemacrophages).OnceinducedtoexpressB7,BcellscanactivatehelperTcells.BcellscantakeupsolubleantigenthroughtheirIgreceptors(unlikedendriticcellsormacrophages).,Theantigenpresentingcells,continued,DendriticCell,Macrophage,Bcell,Note:thisBcellisnotaplasmacell-aplasmacellisshownabove.Plasmacellsdonotpresentantigen.Theysimplypumpoutantibodyforafewdaysthendie.,CaptureofcirculatingTcellsinlymphnodes,Tcellscontinuouslycirculateviathebloodandlymphthroughdifferentlymphnodesuntiltheyeitherfindpresentedantigenoreventuallydie,WhenaTcellencountersanAPCdisplayingantigentowhichitcanbind,itstopsmigratingandbindsstronglytotheAPC.Withinabout2days(48hours),mostantigen-specificTcellshavebeentrappedbyantigenandwithinabout4to5daysarmedeffectorTcellsaremigratingoutofthelymphnode.,Review-CytokinesproducedearlyinresponsetoinfectioninfluencethefuturefunctionsofactivatedCD4+cells,CytokinesproducedbyTH1cellsinhibitTH2cellsCytokinesproducedbyTH2cellsinhibitTH1cellsAnimmuneresponseisoftendominatedbyacell-mediatedresponseoranantibodyresponse.Somepathogenshaveevolvedstrategiestoshifttheimmuneresponsetowardthelesseffectivetypeforthatpathogen.,FunctionsofthedifferentTcelltypes,CD8+cells:KillvirallyinfectedcellsCD4+cells:TH1:Activatemacrophagestoaggressivelyingestantigenandtokillingestedmicrobes.TH2:StimulateBcellstodifferentiateintoantibody-producingplasmacells.BcellswillonlyundergoisotypeswitchingafterreceivingTcellhelp.TheIgclassthataBcellswitchestoisspecifiedbythetypesandbalanceofcytokinessecretedbythehelperTcell.Mostplasmacellsmigratetothebonemarrowwheretheyliveouttherestoftheirlives.,OnecytotoxicTcellcankillmultipletargets,AcytotoxicTcellcausesitstargettoundergoapoptosis(cellsuicide)bythefocussedsecretionofvesiclescarryingcytotoxins.TheTcellbindstoitstarget,deliversitscytotoxins,andmovesonbeforeithasachancetobehurtitself(oneTcellcankillanother,soaTcellisnotimmunetothecytotoxins).,Micrographs:Left:healthycell.Middle:lowerrightcellisinbeginningstageofapoptosisRight:smallcellinmiddleisinadvancedapoptosis.Itsnucleusishighlycondensedandithasshedmuchofitscytoplasm.,Immunologicalmemory,WhenBcellsareactivatedtoreproduce,somedifferentiateintoplasmacellsandsomebecomelong-termmemorycells.AnadaptiveimmuneresponsealsoproducesTcellmemory,butthenatureofmemoryTcellsisunknown.Twopossibilitiesexist.MemoryTcellsprobablyoriginatefromeither:1.Along-livedsubsetofeffectorTcellsthatdifferentiatesintomemoryTcells-likememoryBcells.2.Thecontinuouslow-levelactivationofnaveTcellsbyspecificantigenthatisretainedinthelymphnodesafteraninfection.ThismechanismwouldsuggestthatAPCsinthelymphnodeholdontoantigenonalong-termbasisafteraninfectionandcontinuouslystimulateTcellsatalowlevelsothereisalwaysasmalleffectorpopulationreadytogo.,MHCclassesIandII,Functions:classIMHC:Displayspeptidesderivedfromantigenoriginatinginsidethecell(endogenousantigen).Importantincytotoxicresponses(eg,CD8+-killingofvirus-infectedcells).ClassIIMHC:Displaysantigenderivedfromingestedantigens(exogenousantigen).Importantinhumoral(antibody)responsesaswellinfightingassomeintracellularparasites(eg.MycobacteriumtuberculosisandM.leprae)Locations:ClassIMHCfoundonallnucleatedcells(allcellsneedtobepreparedtobekilledincaseofaviraltake-overortumorigenictransformation).ClassIIMHCfoundonlyonantigenpresentingcells(cellsthatpresentantigentoCD4+Tcells-Macrophages,activatedB-cells,dendriticcells.,AntigenPresentationtoTcells:MHC,AntigensarepresentedtoTcellsasshortpeptidefragmentsboundtoMajorHistocompatibility(MHC)molecules.TwotypesofMHCinhumansandmice:MHCI:presentsan8-10aminoacidpeptidetoCD8+Tcells.MHCII:presentsalongerpeptide(13aaormore)toCD4+Tcells.,Seechapter13:pp103-107,MHCstructure,Seefigure13-5inbook,MHCclassesIandIIhaveanalmostidentical3-Dstructure.BothclassesofMHCarepolygenic(eachcellhasmanyMHCgenes)andpolymorphic(therearemanyallelesforeachlocus),buttheMHCgenesdonotundergorecombination.Note:HumanMHCarecalledHLA(humanleukocyteantigen).,MHC/Tcellinteractions,TheMCH/peptide-TCRinteractionisfacilitatedbytheCD4orCD8co-receptor.,Lookatfigures13-2,13-8and13-10inbook,ClassIIMHC,ClassIMHC,TCRcomplex,CD8,CD8+Tcell,targetcell,CD4,Antigenpresentingcell,TCRcomplex,CD4+Tcell,Antigenprocessing:Endogenouspathway,AllnucleatedcellscanprocessendogenousproteinsandpresentfragmentsontheirclassIMHC.,Endoplasmicreticulum,Nucleus,Cytoplasmicproteins,degradation,VesiclecarryingMHCI-peptide,ProcessinginE.R.andcomplexingwithMHCI,DisplayofMHCI+peptideoncellsurface,Antigenprocessing:Exogenouspathway,Professionalantigenpresentingcellsingestmicrobesandfreeparticles,degradetheminlysozomes,andpresentfragmentstoCD4+TcellsonMHCII.,Endoplasmicreticulum,Nucleus,VesiclecarryingMHCII,MHCIIisassembledinER,DisplayofMHCII+peptideoncellsurface,Ingestionofmicrobe,Degradtioninlysozome,Vesiclefusion,assemblyofpeptide/MHCII,CD4+Tcellactivation,Tcellsrequireco-stimulationforactivation-bindingoftheTCRtoMHC/peptideisnotenoughtoactivateaTcellbyitself.B7onanAPCbindstoCD28ontheTcelltodeliveraco-stimulatorysignal.(seefigure13-8).Activationbypeptide/MHC-TCRbindingplusaco-stimulatorysignalleadstoInterleukin-2(IL-2)releaseandup-regulationoftheIL-2receptorontheTcell.IL-2stimulatesgrowthandproliferationofTcells.,CD8+Tcellactivation,AnavecirculatingCD8+Tcellalsorequiresco-stimulationtobecomean“armed”effectorcell.ACD8+TcellcanbeactivatedbyanAPCdisplayingMHCI/peptidealongwithB7(CD8+cellsalsohaveCD28).ActivationoftheCD8+cellcausesupregulationoftheIL-2receptorandproductionofIL-2,leadingtogrowthandproliferation.AnactivatedCD8+TcellcansustainitselfonitsownIL-2production,onceactivated.,TCRgenetics:SimilartoIggenetics,(numbersofsegmentsinbookisoff,justlikeforIggenes),Seefigure13-4inbook-thenumbersofsegmentsdiffer,buttheorganizationisthesame,chain,chain,MechanismofTCR(orIg)generearrangement.,ThisDNAislostforever,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,ThisDNAislostforever,Rearrangedchain,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,MechanismofTCR(orIg)generearrangement.,Mechan