树突状细胞

2018.11.16Dendriticcells1.Dendriticcells(DCs)areprofessionalantigen-presentingcellsthatinformthefightagainstinvasivepathogenswhileenforcingtolerancetoself-andharmlessenvironmentalantigens.2.Theycapturepathogensandreceivesignalsfrompathogensthatinfluencetheoutcomeofimmuneresponses.Onthebasisofthesesignals,DCsorchestrateantigen-specificT-celldifferentiationtowardTh1,Th2,Th17,orTfhpathways.3.Theycansilenceself-reactiveTcellsbyinducingdeletion,anergy,oractiveregulation(viaregulatoryT[Treg]cells).•ThischapterwillfocusonthefunctionanddevelopmentofDCs,andthemechanismsbywhichtheylinkinnateimmunitytoadaptiveimmunity.DISCOVERY•DCswerediscoveredaspartofanefforttounderstandtheinitiationofimmunity.•Themouseasanexperimentalanimalwascriticalbecauseofasystem,developedbyMishellandDutton,inwhichmousespleencellsuspensionscouldbestimulatedtogenerateantibodyresponsesinculture.小鼠脾脏悬浮细胞刺激产生抗体•Oneoftheearlyobservationswasthatlymphocytesalonewerenotsufficienttoinduceantibody-formingcellresponsesandthatanadherentaccessorycellwasrequired.•ThesearchfortheaccessorycellledtothediscoveryofDCs.What’sTheaccessorycell?单独的淋巴细胞刺激无抗体产生IdentificationandIsolation•DCswerediscoveredbySteinmanandCohnwhentheyexaminedspleenadherentcellsbyphasecontrastmicroscopy.（相差显微镜）•TheythenemployedphysicaltechniquestofractionatespleencellsandpurifyDCs.•Thesecellswerefoundtoadheretoplasticorglass,hadlowbuoyantdensity,anddidnotbindtoerythrocytescoatedwithantibody.（粘附性）•Sequentialstepsofdensitycentrifugation（密度梯度离心）inbovineserumalbumingradientsandadherencetoglasswereoriginallyusedtopurifyDCs.•Atthetime,macrophageswerethoughttobethekeyaccessorycellbecausetheycomposedamajorpopulationofadherentcellsandalsobecausetheirroleininnateimmunityhadbeenlongappreciated.keyaccessorycell•purifiedantigenloadedmacrophagesinducedimmuneresponseswhenreinjectedintotheirhosts.antigenloaded免疫反应But,macrophagesfailedtoshowrobustactivityininductionofantibodyresponsesinvitro,andtheyrapidlydegradedingestedantigenssuggestingthattheywouldbeunabletopresentittolymphocytes.无免疫反应•Atthetime,theprecisefunctionoftheMHCinantigenpresentationwasnotknown,butitwasalreadyclearthattheMHCwasakeygeneticdeterminantofimmuneresponsesandthatitencodedmanyoftheantigensinvolvedingraftrejection.•Themixedleukocytereaction(MLR)wasconsideredaninvitromodelsystemtostudygraftrejectionandwasusedbySteinmanandCohntoexaminethefunctionofDCs.•混合白血球反应mixedleucocytereaction缩写为MLR。将同种动物两个个体的白血球或淋巴细胞混合一起，培养数日，则这些细胞的成细胞化，DNA的合成变得旺盛。将此反应称混合白血球反应或混合淋巴细胞反应（mixedlymphocytereaction）•TheyfoundthatDCswerenearlytwoordersofmagnitudemorepotentthanunfractionatedspleencells,Bcells,ormacrophagesinstimulatingallogeneicTcellsintheMLR.•Onthebasisoftheseexperiments,theyspeculatedthatDCsweretheaccessorycellsthatpresentantigentoTcellstoinitiateimmuneresponses.•However,theirconclusionswerenotwidelyacceptedbyimmunologistsbecauseunliketraditionalimmuneresponses,theMLRdidnotrequirepriming.DC刺激能力强accessorycell•ProofthatDCsareantigen-presentingcellscamefromexperimentsperformedbyNussenzweigandSteinmanwhococulturedDCswithrespondingTcellsandhaptenmodifiedthymocytes.•TheyshowedthatDCsinducedMHC-restrictedcytotoxicTcellsspecifictothehaptenandthatmacrophagesandotherpurifiedpopulationsoflymphoidcellswerenearlyinactiveasaccessorycells.DC反应性T细胞半抗原修饰胸腺细胞MonoclonalAntibodiestoDendriticCells•AseriesofmouseDC-restrictedmonoclonalantibodieswereproducedbySteinmanandothersstartingin1980s,including1.33D1(specificforthecellsurfacereceptorDCIR2/Clec4a4).2.NLDC-145(specificfortheadsorptiveendocytosisreceptor).3.DEC205/clusterofdifferentiation[CD]205).4.N418(specificfortheCD11cintegrin整合素).ThesemonoclonalantibodieswereusedtoestablishtheuniquefunctionsofDCswithinheterogeneousmixturesofleukocytesandtoidentifyDCsinsitu.DendriticCellSubsets•Inthemouse,threemajorgroupsofDCsexistinthesteadystate:plasmacytoidDCs(pDCs),conventionalDCs(cDCs),andmigratoryDCs(mDCs)（1）pDCsareimportantmediatorsofantiviralimmunitythroughtheirabilitytoproducelargeamountsoftypeIinterferons(IFNs)uponviralinfection（2）cDCsarecomposedoftwomajorsubsets,namelyCD8α+andCD8α-，BothcanprocessandpresentantigenstoTcellsandalsosecretecytokinessuchasinterleukin(IL)-12,whichcaninfluencetheultimatepolarizationoftheT-cellresponsetopathogens.（3）mDCsarepresentinnonlymphoidtissuessuchastheliver,gut,skin,lung,andaorta(主动脉),andtheyarecomposedoftwomainsubsetsCD103+andCD103-pDCcDCmDCcDCs（CD8α+andCD8α-）•twosubsetshaveuniquefunctionsinvivoandarenotredundantSomeofthedifferencesincDCsubsetfunctionmaybeaccountedfordifferentialexpressionoftoll-likereceptors(TLRs)orothermediatorsofcDCactivation.SpleenCD8α+cDCexpressTLR3(recognizingdoublestrandedribonucleicacid[RNA])butlackTLR5(recognizingflagellin(鞭毛蛋白))andTLR7(recognizingsingle-strandedRNA),whereasCD8α-cDCsexpressTLR5andTLR7buthavelowlevelsofTLR3.cDCCD8α+TLR3dRNACD8α-TLR5flagellin/TLR7sRNAcDCs（CD8α+andCD8α-）•antigenprocessingcapacityofthetwocDCstypesCD8α+cDCarespecializedforMHCIcross-presentation,andenrichedinTap1,Tap2,calreticulin(钙网织蛋白),calnexin(钙联接蛋白),Sec61,ERp57,ERAAP,aswellascystatin(胱