医学免疫学-主要组织相容性复合体

主要组织相容性复合体

TheMajorHistocompatibilityComplex

(MHC)免疫学系

11OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules21OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules31MHCGeneStructure41MHC结合并递呈抗原肽51MHC结合并递呈抗原肽61T-cellReceptorrecognizesAgdisplayedonMHC71抗原递呈在抗感染免疫中的作用81OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules91TheMouseMHC(H-2)GeorgeSnell(Jacksonlab)InbredmouseSyngeneic(geneticallyidentical)Allogeneic(geneticallydifferent)Congenic(asinglegeneticregionisdifferent)101TissueTransplantation111121131Marker-assistedbackcrossstrategy141TheMouseMHC(H-2)ThemajorhistocompatibilitylocusAntigenIIHistocompatiblity-2(H-2)GraftrejectionMHCTransplantrejectionisTcellmediated.151ThehumanMHC(HLA)JeanDausset,JanvanRoodBloodtransfusion,kidneytransplant,AbHumanleukocyteantigen(HLA)H-2andHLAproteinshaveidenticalstructures.161ImmuneresponsegenesBarujBenacerrafInbredstains--differentAbresponses,Respondervs.non-responderstrainsIr(Immuneresponse)genesmappedtoMHC1711980NobelPrizeBarujBenacerraf,JeanDaussetandGeorgeD.Snell181191DohertyandZinkernagel1996NobelPrize201OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules211HumanMHCChromosome6,3500-4000kb.Containsmorethan200genes.ClassI:HLA-A,B,CClassII:HLA-DP,DQ,DRHLA-A*0201,HLA-DRB1*0401221MHCclassIregion:classic,HLA-A,B,C;non-classic,HLA-E,F,GMHCclassIIregion:DR,DP,DQ;DM,DO;TAP,LMPMHCclassIIIregion:C,CYP21,HSP,TNF,LT,MICA,MICB231MouseMHCChromosome17,2000kb.ClassI:H-2K,H-2D,H-2LClassII:I-A,I-EH-2Kk,H-2Kd,

I-Ad241Haplotype(单体型）ThesetofMHCallelespresentoneachchromosomeHLA-A2,HLA-B5,HLA-DR3H-2dmouse:H-2KdDdLdI-AdI-EdLinkagediseqilibrium251OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules261MHCexpressionClassI–constitutivelyexpressedonallnucleatedcellsClassII–onlyonDC,B,MacMHCexpressionisincreasedbybothinnateandadaptiveimmuneresponsesIFN-α,IFN-β,IFN-γTLRsignalsThemasterregulatorofMHCtranscriptionisclassIItranscriptionactivator(CIITA)271MHCI,allnucleatedcellsMHCII,APCMHCExpression281Peptide-MHCICD8TcellPeptide-MHCIICD4Tcell291KillActivatemacrophagesProduceAbs301OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolymorphismandpolygenyMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules311MHCPolymorphismandPolygeny321MHCPolymorphismandPolygenyPolymorphism:MultiplevariantswithinapopulationHeterozygousforMHCgenesCo-dominantlyexpressedPolygeny:MHCcontainsseveraldifferentclassIandclassIIgenesEveryindividualhasasetofMHCmoleculeswithdifferentrangesofpeptide-bindingspecificity331MHCPolymorphism341351MHCClassIPolymorphism361371MHCpolymorphismextendstherangeofantigenstowhichtheimmunesystemcanrespondMHC,20AAdifference;others,oneorafewEvasivestrategiesofpathogens:Epstein-Barrvirus,HLA-A11,mutantpeptideAdenoviruses,MHC-bindingproteinbindstoapolymorphicregionofMHCIInapopulation,theresponderswereselected.HLA-B53formalariainwestAfrica381391OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules401TwoclassesofMHCmoleculeshavedistinctsubunitcompositionbutsimilar3Dstructures4111.EachMHCmoleculeconsistsofanextracellularpeptidebindinggroove,followedbyIg-likedomain,transmembraneandcytoplasmicdomains.2.Thepolymorphicaminoacidresiduesarelocatedinandadjacenttothepeptide-bindinggroove.3.ThenonpolymorphicIg-LikedomainscontainbindingsitesforCD4andCD8.421Peptidebindinggrooveiscomposedofpairedαhelicesrestingonafloorof8-strandedβ-sheet.431441451Peptide-MHCICD8TcellPeptide-MHCIICD4Tcell461471MHCClassITheαchainandβ2-microglubulin4domains,α1andα2polymorphic,peptidebindinggroove;Endsclose,8-11AAα3andβ2Ig-like,invariantα3conserved,CD8Heterotrimer:αchain,β2-microglubulinandpeptideEachcellhas6differentMHCI481MHCClassIITheαchainandβchain(cisortrans-complementation)α1andβ1peptidebindinggroove;β1hasmostpolymorphism;Endsopen,12-16AA(upto30AA)α2andβ2Ig-like,non-polymorphicβ2CD4Heterotrimer:αchain,βchainandpeptideFromeachparent,DPA,DPB；DQA,DQB；DRA,DRB(2).MHCII>6(10-20)491BindingofpeptidestoMHCmolecules501BindingofpeptidestoMHCmolecules(I)MHCmoleculesshowabroadspecificityforpeptidebinding,incontrasttothefinespecificityofAgrecognitionoftheAgreceptorsoflymphocytes.EachMHCmoleculehasasinglepeptide-bindingcleftthatbindsonepeptideatatime,buteachMHCcanbindmanydifferentpeptides.ThepeptidesthatbindtoMHCmoleculessharestructuralfeaturesthatpromotethisinteraction.Peptidesize:MHCI8-11;MHCII10-30ComplementaryinteractionsbetweenpeptideandMHC511BindingofpeptidestoMHCmolecules(II)MHCmoleculesacquiretheirpeptidecargoduringtheirbiosynthesisandassemblyinsidecells.TheassociationofantigenicpeptidesandMHCmoleculesisstable.Non-covalentinteraction.Verysmallnumbersofpeptide-MHCareabletoactivatespecificT.100complexes(=0.1%MHCII)caninitiateaspecificTcellresponse.MHCdoesnotdiscriminateforeignorselfpeptides.MostMHCsareoccupiedbyselfpeptide.Tcellsareremarkablysensitive.Tcellsforselfpeptide-MHCwerekilledorinactivated.The2ndsignalisrequiredforTcellactivation.521BindingofpeptidestoMHCmolecules531Peptidebinding(MHCClassI)8-10AAPeptidesareboundtoMHCclassImoleculesbytheirends(NH3+,COO-)ConservedresiduesattheendsofMHCIHydrophobic(sometimesbasic)AAattheCterminus2-3AnchorresiduesPeptideelongatedconformationbroadpeptidebindingspecificity541Peptidebinding(MHCClassII)13AAorlonger(13-17)TheendsofpeptidesarenotboundtoMHCclassII.NoconservedresiduesattheendsofMHCIIPeptidesidechainsbindtothebindingcleft;peptidebackbonebindstothesidechainsofAAofbindingcleftPeptideelongatedconformation2Anchorresidues551561571581ManyTCellsRespondtoSuperantigensBindsasanintactproteintotheoutsidesurfaceofMHCIIandVβregionofmanyTCRs.CausesamassiveproductionofcytokinesbyCD4Tcells.SystemictoxicitySuppressionoftheadaptiveimmuneresponseStaphylococcalenterotoxins(SEs)Toxicshocksyndrometoxin-1(TSST-1)591OutlineMHCIntroductionDiscoveryMHCgenestructureExpressionMHCpolygenyandpolymorphismMolecularstructure,bindingofpeptidestoMHCmolecules,MHCrestrictionNon-classicalMHCmolecules601MHCclassIregion:classic,HLA-A,B,C;non-classic,HLA-E,F,GMHCclassIIregion:DR,DP,DQ;DM,DO;TAP,LMPMHCclassIIIregion:C,CYP21,HSP,TNF,LT,MICA,MICB611HLA-E,HLA-G,HLA-FHLA-E(Qa-1)PresentsleaderpeptidesofotherHLAclassImoleculesBindstoNKG2A,inhibitoryreceptorAcellexpressingHLA-EisnotkilledbyNKHLA-GExpressedonfetus-derivedplacentalcellsEngagesNKinhibitoryreceptorLILRB1HLA-FInteractswithLILRB1621MICAandMICBExpressedinfibroblastsandepithelialcellsRecognizedbyNK,γδTcellsandsomeCD8TEngageNKG2D,activationmemberofNK-cellreceptors631641TheCD1familypresentmicrobiallipidstoCD1-restrictedTcells651CD1Human,CD1a,b,c,d,e;Mouse,CD1d1,CD1d2EncodedoutsidetheMHCregionlookslikeMHCI(β2m)BehaveslikeMHCII,bindsitsligandinvesiclesinsteadofERHaveahydrophobicbindinggroovePresentavarietyoflipidsGroup1,CD1a,b,c;Presentsmycolicacid,lipoarabinomannantoαβTcellsGroup2,CD1d;Presentssphingolipids,diacylglycerols,α-Galactoceramide(α-GalCer)toNKTcells661CD1dpresentsglycolipidstoNKTcells671SummaryMHCIntr