滤泡树突状细胞FDC专题汇报

滤泡树突状细胞FDC专题汇报第1页/共42页BACKGROUND第2页/共42页Withinthelymphnodeenvironment,thereisaheterogeneouspopulationofstromalcellsthatarecharacterized,inpart,bytheirdifferentialexpressionofCD31(alsoknownasPECAM1)andpodoplanin(alsoknownasgp38inmiceandgp36inhumans).Thefivemajorstromalcelltypesthatcanbedistinguishedonthebasisoftheirmorphologyandfunctionarefibroblasticreticularcells(FRCs),marginalreticularcells(MRCs),lymphaticendothelialcells(LECs),bloodendothelialcells(BECs)andFDCs.第3页/共42页FDCshavereceivedlittleattentionandinvitrostudiesarechallengingbecauseFDCsarerareandfragile.anunderstandingofFDCsiscriticaltoanunderstandingofGCs,Blymphocytematuration,andoptimalAbresponsesthatarecriticaltoeffectivevaccination.GCsareafundamentalfeatureoftheimmunesystemandpresentationofFDC-AgstoBcellshaspotentialapplications.Rapidresponsesmaybecrucialforprotectingpeopletravelinginareaswithendemicinfections,frombiologicalwarfare,orrapidlyspreadingepidemics.TheabilityofFDCstoproductivelypresentAgtoBcellsshouldadvancethedevelopmentofnewmAbsincludinghumanmAbs.Ontheotherhand,FDC-ICsprobablypromoteautoimmunediseases.第4页/共42页Timelineofmajordiscoveries

intheFDCfield第5页/共42页第6页/共42页Basicoverviewof

lymphnodeandFDC第7页/共42页Folliculardendriticcells(FDCs)areauniquepopulationofcellsthatisessentialforefficientgerminalcentre(GC)formationandfortheproductionofhigh-affinityantibodies1.TheyarecentrallylocatedwithinBcellfolliclesinsecondarylymphoidorgansand,theydevelopfromperivascularprecursorsofstromalcelloriginthatareseededthroughoutthebody.FDCmaturationrequireslymphotoxinandtumournecrosisfactor(TNF)signallingthroughBcells,andthedisruptionofthesepathwaysleadstothelossofFDCs.第8页/共42页第9页/共42页Inthespleenandlymphnodes,FDCsarejustonestromalcelltypewithinanetworkofstromalcells.Althoughincompletelydefined,theinterplaybetweenthesedifferentstromalcellpopulationsmayhavesubstantialeffectsonthegenerationofprotectiveimmunity.第10页/共42页第11页/共42页FDCsarelocalizedtothefolliclesofallsecondarylymphoidtissues,wheretheyretainantigensformonthsintheformofICsTheoriginofFDCsremainsunclear.TherearedatasupportingahematopoieticoriginbutevenmoresupportingastromalcelloriginMorphologically,FDCsareslightlylargerthanlymphocytesandpossessfinedendriticprocessesthatintimatelyinteractwithneighboringcells.Theyhaveirregular,sometimesbilobed,euchromaticnuclei(sometimestherearemultiplenuclei)containingdistinctnucleoli.FDCspossessascantycytoplasmwithfewmitochondria,aroughendoplasmicreticulum,aGolgiapparatusandvesiclesMorphologicaltypesincludeonewithfiliformorfinger-likeprocesses,andonewith‘beaded’dendrites.Thereleasedbeadsarecalled“iccosomes”,whichareimmunecomplex-coatedbodiesor‘somes’第12页/共42页MonoclonalAbsusefulforidentifyingFDCsinclude:FDC-M1&FDC-M2formurineFDCsandDRC-1,HJ2&KI-M4forhumanFDCs

Otherphenotypicmarkersinclude:fcγriib/cd32,FcεRII/CD23,CR1/2/CD21/35,ICAM-1/CD54,VCAM-1/CD106,MadCAM-1,8D6/CD320,CD40,TLR(2,3and4),&lymphotoxinreceptorFDC-cytokinesand–chemokinesinclude:CXCL13,IL-6,IL-7,IL-15,BAFF,andTNF-αFDCsarecriticallyinvolvedingerminalcenterdevelopment,immunoglobulinclassswitching,memoryBcellgeneration,selectionofsomaticallymutatedBcellswithhighaffinityreceptors,affinitymaturation,inductionofrecallresponses,andregulationofserumIgG&IgElevelsInadditiontotheirroleinhumoralimmunity,FDCsareassociatedwithcertaindiseasesincludingHIV/AIDS,priondiseases,follicularlymphomas,andchronicinflammatoryautoimmunediseases第13页/共42页Thegerminalcentrereaction

第14页/共42页FDCshavetheuniqueabilitytoretainintactantigenforextendedperiods.Indeed,thisisrequiredforGCmaintenance,robustBcellsomatichypermutation(SHM)andthepromotionoflong-termimmunememory.ActivatedBcellsthatparticipateinaGCreactioninteractwithantigenonthesurfaceofFDCsinordertoreceivesurvivalsignalsandundergoaffinitymaturation,whichleadstotheformationofmemoryBcellpopulations.第15页/共42页AntigenacquisitionbyFDCs.

第16页/共42页第17页/共42页FDCsandBcell第18页/共42页AFDCs:beyondthenecessityofT-cellhelp(2001)BActivationofBcellsbyantigensonFDCs(2010)CL-21-dependentBcelldeathdrivenbyFDCs(2011)EHumanFDCspromotetheAPCcapabilityofBcells(2012)DFDCspromoteBcellretentioningerminalcenters(2011)FImmuneregulationbyFcα/μreceptor(CD351)onmarginalzoneBcellsandFDCs(2012)GFDCActivationbyTLRLigandsPromotesAutoreactiveBCellResponses.(2017)第19页/共42页FDCs:beyondthenecessityofT-cellhelpFolliculardendriticcells(FDCs)arepotentaccessorycellsforBcells,。TheengagementofCD21intheB-cellcoreceptorcomplexbycomplement-derivedCD21ligandonFDCsdeliversacrucialsignalthatdramaticallyaugmentsthestimulationdeliveredbythebindingofantigentotheB-cellreceptor(BCR).FDCsminimizeanegativeB-cellsignal.Inshort,theseligand–receptorinteractionshelptosignaltoBcellsandmeetarequirementforB-cellstimulationthatgoesbeyondthenecessityofT-cellhelp.第20页/共42页第21页/共42页ActivationofBcellsbyantigensonfolliculardendriticcellsAneedforantigen-processingandpresentationtoBcellsisnotwidelyappreciated.However,cross-linkingofmultipleBcellreceptors(BCRs)byT-independentantigensdeliversapotentsignalthatinducesantibodyresponses.SuchBCRcross-linkingalsooccursingerminalcenterswherefolliculardendriticcells(FDCs)presentmultimerizedantigensasperiodicallyarrangedantigen-antibodycomplexes(ICs).Certainantigens(Ag)canengageBcellssuchthatspecificantibodies(Abs)areinducedintheabsenceofTcellhelp.Theseso-calledTcell-independent(TI)AgsarefurtherclassifiedintoTItype1and2.FDCstrapimmunecomplexes(ICs),andAginFDC-ICsareintactandpersistinaformthatcanberecognizedbyspecificantibodiesformonthsorevenyears第22页/共42页第23页/共42页ModelofFDC-dependentbutT-independentBcellactivationandIgproduction第24页/共42页TindependentBcellactivationbyIC-bearingFDCs第25页/共42页RobustGCsandplasmablastresponsesinducedin48hinnudemicebyOVA-ICsinassociationwithIC-retainingFDC-reticula第26页/共42页IL-21-dependentBcelldeathdrivenbyprostaglandinE2,aproductsecretedfromfolliculardendriticcells·Ingerminalcenters(GCs),BcellsareselectedthroughinteractionwithfolliculardendriticcellsbearingimmunecomplexesandfollicularhelperT(Tfh)cellssecretingTfhcytokines,includingIL-21.·FL-YBcellsefficientlyenhancedviabilityofcoculturedmouseBcellsinaBAFF-dependentfashion.···AdditionofIL-21,amajorTfhcytokine,readilyinduceddeathofBcellsthatwerecoculturedwithFL-YBcells,whereasIL-21alonesustainedviabilityofBcellsintheabsenceofFL-YBcells.TheIL-21–induceddeathwasdependentonalowm.w.solublefactorthatwasreleasedfromFL-YBcells,whichwasfinallyidentifiedasPGE2.TreatmentofBcellswithIL-21plusPGE2,butnoteitheralone,resultedinenhancedexpressionofaproapoptoticproteinBimandtheupstreamtranscriptionfactorFoxo1.APGE2receptorisoform,EP4,wasresponsibleforIL-21/PGE2–inducedBcelldeath.第27页/共42页IL-21inducesBcelldeathinthepresenceofFDCs第28页/共42页第29页/共42页IdentificationoftheFL-YB–derivedfactorresponsibleforIL-21–inducedBcelldeath第30页/共42页MechanismofactionofPGE2ininducingdeathofIL-21–stimulatedBcells第31页/共42页FollicularDendriticCellActivationbyTLRLigandsPromotesAutoreactiveBCellResponsesHumanfolliculardendriticcellspromotetheAPCcapabilityofBcellsbyenhancingCD86expressionlevelsImmuneregulationbyFcα/μreceptor(CD351)onmarginalzoneBcellsandfolliculardendriticcellsCo-stimulatoryfunctioninprimarygerminalcenterresponses:CD40andB7arerequiredondistinctantigen-presentingcells第32页/共42页FDCsandHIV第33页/共42页FollicularDendriticCellsRetainInfectiousHIVinCyclingEndosomes·

Folliculardendriticcells(FDC)areindirectcontactwithCD4+Tcellsandtheyretainintactantigenforprolongedperiods.·DespitethesuccessofART,itdoesnotcureHIVanddiscontinuationresultsinviralrebound.Folliculardendrit