免疫学-T细胞活化机制(英文)

T细胞活化机制

免疫学系基础医学院

2023/2/151NaïveTcellsMatureTcellsthathavenotpreviouslyencounteredantigen;Preferentialmigrationtosecondarylymphoidorgans(lymphnodes),wheretheyrecognizeantigenEffectorTcellsActivatedTcellscapableofperformingthefunctionsrequiredtoeliminateforeignantigensPreferentialmigrationtositesofinfectionorinflammationShort-livedMemoryTcellsLong-lived,functionallysilentcells;MountrapidsecondaryimmuneresponsestothesameantigenexposureHeterogenous(centralandeffector)BasedonthehistoryofantigenencounterandthestageofTcellactivation.2023/2/152应答诱导外周淋巴器官内抗原识别T细胞扩增和分化分化的细胞进入循环效应T细胞和其他白细胞迁移到感染部位在外周效应T细胞遭遇抗原效应T细胞活化T细胞的效应功能2023/2/153.ActivationofTcellschangestheexpressionofseveralcell-surfacemolecules2023/2/154FunctionalresponsesofTcellsSecretionofcytokinesProliferationDifferentiationintoeffectorTcellsDifferentiationintomemoryTcells2023/2/155SecretionofcytokinesOneoftheearliestdetectableresponsesofTcellstoantigenrecognitionPrinciplecytokine:IL-2DistinctsetsofcytokinessecretedbyeffectorTcells2023/2/156ClonalexpansionofTcells2023/2/157Antigen-presentingcellsarerequiredforTcellactivation2023/2/158SpecificantigenrecognitionbytheTcells;StableadhesionoftheTcellstotheAPCs;TransductionofactivatingsignalstotheTcells.TheinitiationofTcellresponsestospecificantigenrequiresEachoftheseeventsismediatedbydistinctsetsofmoleculesontheTcells.

2023/2/159Tcellreceptorsandaccessorymolecules2023/2/1510Tcellreceptor(TCR)ThedefinitiveTcelllineagemarker

RecognitionofMHC-associatedpeptideantigen

DualspecificityMHCrestrictionAntigenspecificityNosignal-transducingfunctions2023/2/1511TCRcomplexComposedofTCRandCD3

protein

2023/2/1512invariantprotein,identicalinallTcellsregardlessofspecificityresponsibleforsignaling,butnotantigenrecognitionImmunoreceptortyrosine-basedactivationmotif

（ITAM)CD3Containstwocopiesofaconservedsequence:

tyrosine-X-X-leucine/isoleucineImportantforsignaltransductioninTcells2023/2/1513AntigenrecognitionandsignalingfunctionsofTcellsAntigenrecognitionSignalingfunctions2023/2/1514Co-receptorsCD4andCD8MatureTcellsexpresseitherCD4orCD8,butnotbothInvolvedinMHC-restrictedTcellactivationCD4ClassⅡMHCmoleculesCD8ClassⅠMHCmoleculesAcategoryofmembraneproteinsthatenhanceTCRsignalingthroughsimultaneousbindingoftheMHCmolecules2023/2/15152023/2/1516Two-signalHypothesis2023/2/1517Signal1TCR-MHC+Aginteractionnotenoughforfullactivation2023/2/1518OverviewofTCRsignallingNatureReviewImmunol2013threemajorsignallingpathways2023/2/1519ProvidedbyCostimulatoryMoleculesonactivatedAPCsAPCTCellB7CD28Signal2B7.1(CD80)B7.2(CD86)promotethesurvivalandexpansionoftheTcells2023/2/1520AcomparisonbetweensignallingpathwaysinfullystimulatedandinanergizedTcellsdefectsatvariouspointsintheMAPK(mitogen-activatedproteinkinase)pathwaydownstreamofco-stimulationFathmanandLineberry,2007,NatureImmunology2023/2/1521Functionsofco-stimulatorsinTcellactivationCyclosporinAFK506Rapamycin2023/2/1522High-affinityIL-2receptorsarethree-chainstructuresthatarepresentonlyonactivatedTcells2023/2/1523MediatedprimarilybyanautocrinegrowthpathwayProliferation2023/2/1524ClonalexpansionThefrequencyofnaïveTcellsspecificforagivenantigenis~1:105-6Ag-specificCD8+Tcells1:10

Ag-specificCD4+Tcells1:100/1000Ag-specificmemoryTcells1:104Agiseliminated2023/2/1525PhasesofTcellresponsespriming2023/2/15262023/2/1527Variationinsignal3causesnaiveCD4Tcellstoacquireseveraldistincttypesofeffectorfunctions2023/2/1528AmodelfortheregulationofearlyTH2differentiationbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology2023/2/1529AmodelforearlydeterminationofiTregfateversusTH17fatecontrolledbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology2023/2/1530AmodelforearlydeterminationofTeffcellfateversusTfhcellfatecontrolledbyTCRsignalstrengthHidehiroYamane&WilliamEPaul,2012NatureImmunology2023/2/1531Co-signalingreceptors

CD28ICOSCTLA-4PD-1CD40LOX40LMembraneproteinsexpressedonTcellsparticipateinresponsestoantigenbyrecognizingco-stimulators

orco-inhibitors

onAPCs,butnotrecognizingantigenTheIgsuperfamilyTNFreceptorsuperfamily2023/2/1532CD28ThediscoveryofCD28asaprototypeco-stimulatoryTCRprovidedevidenceforthetwo-signalmodelofTcellactivation,Firstidentifiedco-stimulatoryreceptortorecognizeB7moleculesonAPCsPrincipalreceptorfordeliveringsecondsignalsforTcellactivation2023/2/1533B7moleculesBest-definedco-stimulatorsIncludeB7.1(CD80)andB7.2(CD86)ExpressedmainlyonAPCs

IncreasedbymicrobialproductsandcytokinesImportantfortheactivationofnaïveTcellsbyinteracting

with

CD28onTcells2023/2/1534ICOS(Inducibleco-stimulator)

ExpressedonactivatedTcellsBindsICOSL(ICOSligandorB7-H2)

Importantfortheactivationofeffectorcellstosecretesome

cytokines,suchasIL-4andIFN-

particularlyimportantfroenablingCD4TcellstohelpercellsforB-cellresponsessuchasisotypeswitching2023/2/1535CTLA-4ExpressedonrecentlyactivatedTcellscompetewithCD28fortheligandsCD80andCD86(with20Xhigheraffinity)

ActsasasignaldampenerduringtheearlystagesofactivationofnaïveandmemoryTcells(24-48hrafterantigenpresentation)

Playacentralroleinself-tolerance2023/2/1536MechanismsofactionoftheinhibitoryreceptorCTLA-4CompetitivelybindtoB7Generateinhibitorysignal2023/2/1537Forthediscoveryanddevelopmentofamonoclonalantibodytherapythatunleashestheimmunesystemtocombatcancer.科学很有意思，但同时也很艰辛。我认为现在让年轻科学家们去研究转化科学，做一些很快能应用到临床上的研究，会给他们施加过多压力。他们应该做的事情，是在基础生物学领域提出一些重要问题，并时不时地思考一下它们是怎样影响人体健康的，而不要把所有时间都花费在试图“解决健康问题”上。我认为，真正好的基础研究始终能占据一席之地。2023/2/1538PD-1(Programmeddeath-1)

ExpressedonactivatedTcellsaswellasBcellsandNKcells

ItsligandsPD-L1andPD-L2expressedbyinflammatorytissuesandcancercells.

Inhibitechronicallyactivatedcellsandresponsesinperipheral,non-lymphoidtissues2023/2/1539TheB7-CD28familiesofco-stimulatorsandco-inhibitoryreceptors2023/2/1540CD40LMemberofTNFsuperfamilyExpressedonactivatedTcellsBindstoCD40expressedonAPCsIndireclyamplifyTcellresponsesbyenhancingtheexpressionof

B7moleculesinAPCs2023/2/1541RoleofCD40inTcellactivation.2023/2/1542LiepingChenandDallasB.Flies,2013NatureImmunologyReview2023/2/1543Co‑stimulatoryandco‑inhibitorysignallingpathwaysdownstreamofCD28familyreceptors.LiepingChenandDallasB.Flies,2013NatureImmunologyReview2023/2/1544TheseverallevelsofregulationinTcellco-signaling

Spatiotemporalregulationofco-signaling

Differentialinteractionsthroughmultipleinterfaces.2023/2/1545重大疾病免疫治疗的时代已经来临Science：重大疾病免疫疗法是2013年最值得关注的六大科学领域之一免疫细胞治疗展现惊人疗效，权威期刊的纷纷评述免疫治疗的成就2023/2/1546StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycle癌细胞抗原的释放癌抗原的提呈肿瘤抗原特异性T细胞的

致敏与活化T细胞迁移到肿瘤T细胞的肿瘤局部浸润T细胞识别癌细胞杀伤癌细胞2023/2/1547第二代抗体之一：抗肿瘤单克隆抗体(CTLA-4mAb)2023/2/15482023/2/1549第二代抗体之二：抗肿瘤单克隆抗体(PD-1/PD-L1mAb)Anti-PD-1mAbAnti-PD-L1mAb2023/2/1550TheactivationofCD8+Tcells

Requirebothantigenrecognitionandsecondsignals

MayrequiresecondsignalprovidedbyCD4Thcells

intheconditionsthattendtoelicitweakinnateimmunereactions

latentviralinfectionorgantransplantstumor

2023/2/1551Roleofco-stimulationandhelperTcellsintheCD8+Tcelldifferentiation2023/2/1552HierarchicalTcellexhaustionduringchronicinfection2023/2/1553SubsetsofexhaustedTcellsandcombinatorialstrategiestoreverseexhaustion2023/2/1554AcutoO,VDBartolo,andFMichel.TailoringT-cellreceptorsignalsbyproximalnegativefee