tlr2 stimulation strengthens intrahepatic myeloid-derived cell-mediated t cell tolerance through inducing kupffer cell expansion and il-10 production jia liu论文.pdf

该【tlr2 stimulation strengthens intrahepatic myeloid-derived cell-mediated t cell tolerance through inducing kupffer cell expansion and il-10 production jia liu论文 】是由【小舍儿】上传分享，文档一共【12】页，该文档可以免费在线阅读，需要了解更多关于【tlr2 stimulation strengthens intrahepatic myeloid-derived cell-mediated t cell tolerance through inducing kupffer cell expansion and il-10 production jia liu论文 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。:..TLR2StimulationStrengthensIntrahepaticMyeloid-DerivedCell-MediatedTCellTolerancethroughInducingKupfferCellExpansionandIL-10ProductionThisinformationiscurrentasofFebruary19,,QingYu,WeiminWu,XuanHuang,RuthBroering,MelanieWerner,MichaelRoggendorf,DongliangYangandMengjiLuJImmunolpublishedonline19February2018tent/early/2018/02/16//?Submitonline.?RapidReviews!30days*fromsubmissiontoinitialdecision?NoTriage!EverysubmissionreviewedbypracticingscientistsbyguestonFebruary19,2018?FastPublication!eptancetopublication*averageSubscriptionInformationaboutsubscribingtoTheJournalofImmunologyisonlineat:/subscriptionPermissionsSubmitcopyrightpermissionrequestsat:ut/Publications/JI/-:/alertsTheJournalofImmunologyispublishedtwiceeachmonthbyTheAmericanAssociationofImmunologists,Inc.,1451RockvillePike,Suite650,Rockville,MD20852Copyright?2018byTheAmericanAssociationofImmunologists,:0022-1767OnlineISSN:1550-6606.:..PublishedFebruary19,2018,doi:-DerivedCell-MediatedTCellTolerancethroughInducingKupfferCellExpansionandIL-10ProductionJiaLiu,*,?,1QingYu,?,1WeiminWu,*XuanHuang,*RuthBroering,?MelanieWerner,?MichaelRoggendorf,*DongliangYang,?andMengjiLu*,wehavedemonstratedthatTLR2stim-,,weinvestigatedwhetherTLR2stimulationin?uencesthefunctionofintrahepaticmyeloid-derivedcells(iMDCs)andelu-cidatedthemechanismsinvolvediniMDC-?,insteadofinducingcellfunctionalmaturation,TLR2ligandpalmitoyl-3-cysteine-serine-lysine-4(P3C),thepopulationofKupffercells(KCs)--mediatedCD8Tcellinhibitionwasmediatedbysolublemediators,oneofwhichwasIL--10blockadecouldpartiallyabolishiMDC-mediatedTcellinhibition./Moreover,hepatitisBvirusparticlestimulationoniMDCscouldalsoinduceIL-10productionbythecellsinaTLR2--speci?,2018,200:000?(suchasalllivernonparenchymalcells,liversinusoidalendothelialcellshepatitisviruses)evadeimmuneclearanceandachieve(LSECs)andintrahepaticmyeloid-derivedcells(iMDCs)(6).theliverisinvolvedinthechronicityofthesepathogeninfections(1).TheiMDCs,monlyCD11bpositive,includebyguestonFebruary19,2018ManystudieshavedocumentedfunctionsoftheliverinducingimmuneKupffercells(KCs)(F4/80+,CD11b+)(7),ellstoleranceratherthanresponsestoAgsencounteredlocally(2).These(DCs)(CD11b+,CD11c+,CD8a2,B2202)(6),someNKcells,-residentparenchymalandnonparenchymalAPCs(3?5).Amonglargestmacrophagepopulationintheliverandexpresssigni?cantlylowerlevelsofMHC-IIandcostimulatorymoleculessuchasB7-1,B7-2,andCD40(-*InstituteforVirology,UniversityHospitalEssen,UniversityofDuisburg-Essen,?viousstudiesreportedthatKCsarecriticalforportalveintolerance45147Essen,Germany;DepartmentofInfectiousDiseases,UnionHospital,Tongji(9),liverallografttolerance(10),andtoleranceagainstsolubleAgsMedicalCollege,HuazhongUniversityofScienceandTechnology,Wuhan430022,?China;andDepartmentofGastroenterology,UniversityHospitalEssen,University(11).Comparedtothosefromsecondarylymphoidtissue,myeloidofDuisburg-Essen,45147Essen,GermanyDCspuri?edfromliverarelessmature,(12,13).TheyarepoorstimulatorsofnaiveallogeneicORCID:0000-0003-3293-6738(.).TcellsandofTh1cellpolarizationbutpromoteTh2cellskewing(1).ReceivedforpublicationApril17,,,asagroupofhighlyconservedmolecules,playamajorThisworkwassupportedbygrantsfromtheDeutscheForschungsgemeinschaftroleintherecognitionofpathogen-associatedmolecularpatterns(TRR60)andtheNationalNaturalScienceFoundationofChina(81461130019,anisms(14).91642118,and91742114).Throughsensingtheirligands,TLRstriggermanyantiviralmech-.,.,.,.,.,andanismsincells,includingtheproductionofin?.,.,.,.,.,.,andthematurationofAPCs(15,16).Thus,TLRsserveasanim-.,.,.,,portantlinkbetweeninnateandadaptiveimmunity(17).Wehavetechnical,,InstituteforVirol-suppressivepropertiestoinduceTcellimmunity(18).However,ogy,UniversityHospitalEssen,Hufelandstrasse55,45147Essen,-mailaddress:mengji.******@uni--,:DC,ell;FV,Friendvirus;HBV,hep-TLR2wasreportedtorecognizevirallipoproteinsandglyco-atitisBvirus;HI,hydrodynamicinjection;iMDC,intrahepaticmyeloid-derivedcell;,Kupffercell;LSEC,liversinusoidalendothelialcell;P3C,palmitoyl-3-cysteine-thathepatitisBcoreAgtriggerstheproductionofin?ammatoryserine-lysine-4;tg,transgenic;Treg,,suchasTNF-a,IL-6,andIL-12bymacrophagesCopyrightó2018byTheAmericanAssociationofImmunologists,-1767/18/$-dependentmanner(19).Lietal.(20)performedthe/doi/:..2TLR2-INDUCEDSUPPRESSIVEEFFECTSOFKCSONTCELLACTIVATIONhydrodynamicinjection(HI)ofthehepatitisBvirus(HBV)genomepolycarbonatemembrane;BDLabware,Heidelberg,Germany),andspleno-icde?ciencyinTLR2improvedHBVelim-,whereasactivatingTLR2ledtoamorestableHBVper-AnalysisofCD8++stimulationcouldactivateTLR2andinduceIL-10productionbyCFSE(Invitrogen,Darmstadt,Germany)-labeledFVTCRtgCD8Tcells+werecoincubatedwithiMDCsorDCsinthepresenceofAgfor3dandKCs,whichsupportlivertolerancebyinducinganti-HBVCD8analyzedforactivation/proliferationby?(20).ofthematurationofiMDCfunction,correspondingpeptide-loadediMDCs+Inthecurrentstudy,,cytokineconcen-,intracellularTcellactivationaswellasthepossibilityofHBVenrollingtheIFN-hepercentageofIFN-g?++TcellstoiMDCs/DCswas2:-,aone-wayANOVAwasusedwithaTukeyposthoctest(GraphPadPrismsoftware;raphPad,SanDiego,CA).theCareandUseofLaboratoryAnimalsandwereapprovedbythelocalmittee(AnimalCareCenter,UniversityofResultsDuisburg-Essen,Essen,GermanyandthedistrictgovernmentofDusseldorf,iMDCssuppressTcellIFN-gproductionandproliferationinaGermany).Thestudyconformstotheethicalguidelinesofthe1975Dec-DownloadedfromlarationofHelsinkiandwasapprovedbytheInstitutionalReviewBoardcellcontact–independentmanner(mittee)ofthemedicalfacultyattheUniversityofDuisburg-EssenFortheinitialassessmentoftheimmunosuppressivepropertiesofmitteeatTongjiMedicaliMDCs,Tcellsstimulatedwithanti-CD3andanti-CD28wereCollege,HuazhongUniversityofScienceandTechnology,--InbredC57BL/6wild-typeandDbGagLTCRtransgenic(tg)micewerebredanddition,activatedTcellsproducedsigni?cantlylessIFN-ginthe/keptatspeci?cpathogen-().Next,weexaminedtheconsequenceofC57BL/()background,and90%oftheCD8+AgpresentationbyiMDCstoinduceAg-D8+Tcellre-TcellscontainedaTCRspeci?cfortheDbGagLFriendvirus(FV)epitope(FVsponsebyusingTCRtgCD8+Tcellsspeci?ctotheDbGagLFVTCRCD8+Tcells)(21).Allmicewerefemales,8?10wkofage,andwere++keptintheAnimalCareCenter,UniversityofDuisburg-Essen(Essen,Ger-epitope(FVTCRCD8Tcells)(21).NaiveFVTCRCD8Tcellsmany)andtheAnimalCareCenterofTongjiMedicalCollege(Wuhan,China).werecoculturedwithepitopepeptide-loadediMDCsorbonemar-row??ReagentsandAbsderivedDCs,TcellsprimedbyiMDCsshowedsigni?cantlylessIFN-AgonistsforTLR2(palmitoyl-3-cysteine-serine-lysine-4[P3C])werepur-gproductionandproliferationinresponsetoPMAandionomycinchasedfromInvivoGen(SanDiego,CA).NeutralizingAbsanti?IL-10Rwererestimulation(),indicatingtheabilitytoinduceCD8+TcellbyguestonFebruary19,2018providedbyeBioscience(SanDiego,CA).-mediatedHIinmicesuppressionofTcellfunctionsiscellcontact?dependent,poly-,malemiceatclonalactivatedTcellswerecoculturedwithiMDCsinthetranswell6?8wkofagewerehydrodynamicallyinjectedwith10mgpAAV/---gproductionbyiMDCs().(22).iMDCswerethenpuri?edfromnonparenchymalliver+TLR2stimulationstrengthensthesuppressiveandtolerogenicordingtothemanufac-+propertiesofiMDCsinacellcontact–independentmannerturer?(18).PrimaryhumanKCswerepreparedfromnon-Next,weinvestigatedhowTLR2stimulationmodulatesthesup-(23).Thepuritiesofthecellfractionsweremonitoredby?owcytometryandmicewerepretreatedwithorwithoutTLR2ligandP3Cfor24handwereover90%,5%,P3C-pretreatediMDCsshowedanenhancedFlowcytometryabilityinsuppressingactivatedTcellproliferationandIFN-gCellsurfaceandintracellularstainingfor?owcytometryanalysiswasproduction().ThisenhancedsuppressionofTcellIFN-gperformedusingBDBiosciences(Heidelberg,Germany)oreBioscienceproductionbytheP3C-stimulatediMDCswasmaintainedinthe(Frankfurt,Germany)-gstainingwasperformedtranswellsystem,indicatingthattheeffectwasmediatedbysolubleasdescribedpreviously(24).DatawereacquiredusingaFACSCantoIIfactors().However,thesuppressionofsplenocyteprolifera-?owcytometer(BDBioscienc