濾泡樹(shù)突狀細(xì)胞FDC專題匯報(bào)第1頁(yè)/共42頁(yè)BACKGROUND第2頁(yè)/共42頁(yè)Withinthelymphnodeenvironment,thereisaheterogeneouspopulationofstromalcellsthatarecharacterized,inpart,bytheirdifferentialexpressionofCD31(alsoknownasPECAM1)andpodoplanin(alsoknownasgp38inmiceandgp36inhumans).Thefivemajorstromalcelltypesthatcanbedistinguishedonthebasisoftheirmorphologyandfunctionarefibroblasticreticularcells(FRCs),marginalreticularcells(MRCs),lymphaticendothelialcells(LECs),bloodendothelialcells(BECs)andFDCs.第3頁(yè)/共42頁(yè)FDCshavereceivedlittleattentionandinvitrostudiesarechallengingbecauseFDCsarerareandfragile.anunderstandingofFDCsiscriticaltoanunderstandingofGCs,Blymphocytematuration,andoptimalAbresponsesthatarecriticaltoeffectivevaccination.GCsareafundamentalfeatureoftheimmunesystemandpresentationofFDC-AgstoBcellshaspotentialapplications.Rapidresponsesmaybecrucialforprotectingpeopletravelinginareaswithendemicinfections,frombiologicalwarfare,orrapidlyspreadingepidemics.TheabilityofFDCstoproductivelypresentAgtoBcellsshouldadvancethedevelopmentofnewmAbsincludinghumanmAbs.Ontheotherhand,FDC-ICsprobablypromoteautoimmunediseases.第4頁(yè)/共42頁(yè)Timelineofmajordiscoveries

intheFDCfield第5頁(yè)/共42頁(yè)第6頁(yè)/共42頁(yè)Basicoverviewof

lymphnodeandFDC第7頁(yè)/共42頁(yè)Folliculardendriticcells(FDCs)areauniquepopulationofcellsthatisessentialforefficientgerminalcentre(GC)formationandfortheproductionofhigh-affinityantibodies1.TheyarecentrallylocatedwithinBcellfolliclesinsecondarylymphoidorgansand,theydevelopfromperivascularprecursorsofstromalcelloriginthatareseededthroughoutthebody.FDCmaturationrequireslymphotoxinandtumournecrosisfactor(TNF)signallingthroughBcells,andthedisruptionofthesepathwaysleadstothelossofFDCs.第8頁(yè)/共42頁(yè)第9頁(yè)/共42頁(yè)Inthespleenandlymphnodes,FDCsarejustonestromalcelltypewithinanetworkofstromalcells.Althoughincompletelydefined,theinterplaybetweenthesedifferentstromalcellpopulationsmayhavesubstantialeffectsonthegenerationofprotectiveimmunity.第10頁(yè)/共42頁(yè)第11頁(yè)/共42頁(yè)FDCsarelocalizedtothefolliclesofallsecondarylymphoidtissues,wheretheyretainantigensformonthsintheformofICsTheoriginofFDCsremainsunclear.TherearedatasupportingahematopoieticoriginbutevenmoresupportingastromalcelloriginMorphologically,FDCsareslightlylargerthanlymphocytesandpossessfinedendriticprocessesthatintimatelyinteractwithneighboringcells.Theyhaveirregular,sometimesbilobed,euchromaticnuclei(sometimestherearemultiplenuclei)containingdistinctnucleoli.FDCspossessascantycytoplasmwithfewmitochondria,aroughendoplasmicreticulum,aGolgiapparatusandvesiclesMorphologicaltypesincludeonewithfiliformorfinger-likeprocesses,andonewith‘beaded’dendrites.Thereleasedbeadsarecalled“iccosomes”,whichareimmunecomplex-coatedbodiesor‘somes’第12頁(yè)/共42頁(yè)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頁(yè)/共42頁(yè)Thegerminalcentrereaction

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

第16頁(yè)/共42頁(yè)第17頁(yè)/共42頁(yè)FDCsandBcell第18頁(yè)/共42頁(yè)AFDCs:beyondthenecessityofT-cellhelp(2001)BActivationofBcellsbyantigensonFDCs(2010)CL-21-dependentBcelldeathdrivenbyFDCs(2011)EHumanFDCspromotetheAPCcapabilityofBcells(2012)DFDCspromoteBcellretentioningerminalcenters(2011)FImmuneregulationbyFcα/μreceptor(CD351)onmarginalzoneBcellsandFDCs(2012)GFDCActivationbyTLRLigandsPromotesAutoreactiveBCellResponses.(2017)第19頁(yè)/共42頁(yè)FDCs:beyondthenecessityofT-cellhelpFolliculardendriticcells(FDCs)arepotentaccessorycellsforBcells,。TheengagementofCD21intheB-cellcoreceptorcomplexbycomplement-derivedCD21ligandonFDCsdeliversacrucialsignalthatdramaticallyaugmentsthestimulationdeliveredbythebindingofantigentotheB-cellreceptor(BCR).FDCsminimizeanegativeB-cellsignal.Inshort,theseligand–receptorinteractionshelptosignaltoBcellsandmeetarequirementforB-cellstimulationthatgoesbeyondthenecessityofT-cellhelp.第20頁(yè)/共42頁(yè)第21頁(yè)/共42頁(yè)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頁(yè)/共42頁(yè)第23頁(yè)/共42頁(yè)ModelofFDC-dependentbutT-independentBcellactivationandIgproduction第24頁(yè)/共42頁(yè)TindependentBcellactivationbyIC-bearingFDCs第25頁(yè)/共42頁(yè)RobustGCsandplasmablastresponsesinducedin48hinnudemicebyOVA-ICsinassociationwithIC-retainingFDC-reticula第26頁(yè)/共42頁(yè)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頁(yè)/共42頁(yè)IL-21inducesBcelldeathinthepresenceofFDCs第28頁(yè)/共42頁(yè)第29頁(yè)/共42頁(yè)IdentificationoftheFL-YB–derivedfactorresponsibleforIL-21–inducedBcelldeath第30頁(yè)/共42頁(yè)MechanismofactionofPGE2ininducingdeathofIL-21–stimulatedBcells第31頁(yè)/共42頁(yè)FollicularDendriticCellActivationbyTLRLigandsPromotesAutoreactiveBCellResponsesHumanfolliculardendriticcellspromotetheAPCcapabilityofBcellsbyenhancingCD86expressionlevelsImmuneregulationbyFcα/μreceptor(CD351)onmarginalzoneBcellsandfolliculardendriticcellsCo-stimulatoryfunctioninprimarygerminalcenterresponses:CD40andB7arerequiredondistinctantigen-presentingcells第32頁(yè)/共42頁(yè)FDCsandHIV第33頁(yè)/共42頁(yè)FollicularDendriticCellsRetainInfectiousHIVinCyclingEndosomes·

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