activation of dendritic cells

DendriticcellsDendriticcells(DCs)areasparselydistributed,migratorygroupofbone-marrow-derivedleukocytesthatarespecializedfortheuptake,transport,processingandpresentationofantigenstoTcellsSubtypesOfDCsActivationofDCsAtan‘immature’stageofdevelopment,DCsactassentinelsinperipheraltissues,continuouslysamplingtheantigenicenvironment(FIG.1).AnyencounterwithmicrobialproductsortissuedamageinitiatesthemigrationoftheDCstolymphnodes(LNs).TheantigenicsampleatthetimeoftheDANGER,includinganymicrobialproducts,isprocessedandfixedontheDCsurfaceaspeptidesthatarepresentedbymajorhistocompatibilitycomplex(MHC)molecules.TheDCsalsoupregulatetheco-stimulatorymoleculesthatarerequiredforeffectiveinteractionwithTcells.ActivationofDCs..Microbialinfection,inflammationandtissuedamageallactivatetheDCsandincreasetheirrateofmigrationintolymphoidtissue,wheretheysignaltoTcellsthatarespecificfortheforeignantigensthatarepresentedbytheDCstoinitiateimmuneresponses..ThesemodelsrequiretheDCstosense‘danger’intheformofmicrobesortissuedamage.ThemicrobialproductswhichcanactivateDCseffectivelyinclude:LPS,CPGmotifs,PGN,LTA,cylicglucans,poly(I:C),double-strandedviralRNA,Choleratoxin(CT)andsoon.LPSLPSinducescostimulatoryactivityforCD4+TcellsonBlymphocytesandmacrophages(66),andtriggersmaturationandmigrationofDCinvivo(Regulationofdendriticcellnumbersandmaturationbylipopolysaccharideinvivo.J.Exp.Med.1996.184:1413–1424.)CpGmotifSimilartolipopolysaccharide,i.s.CpG-ODNcausedup-regulationofMHCclassII,CD40andCD86,butnotCD80onimmatureandmatureDC.InparallelbothDCsubsetswereactivatedtoproducelargeamountsofIL-12,IL-6andTNF.(BacterialDNAandimmunostimulatoryCpGoligonucleotidestriggermaturationandactivationofmurinedendriticcells.Eur.J.Immunol.28,2045–2054(1998).)CylicGlucansTheBrucellacyclicglucansshowedneithertoxicitynorimmunogenicitycomparedtoLPSandtriggeredantigen-specificCD8+Tcellresponsesinvivo.Thesecyclicglucansalsoenhancedantigen-specificCD4+andCD8+TcellresponsesincludingcrosspresentationbydifferenthumanDCsubsets.Brucellab1,2cyclicglucansincreasedthememoryCD4+Tcellresponsesofbloodmononuclearcellsexposedtorecombinantfusionproteinscomposedofanti-CD40antibodyandantigensfrombothhepatitisCvirusandMycobacteriumtuberculosis.(Brucellab1,2CyclicGlucanIsanActivatorofHumanandMouseDendriticCells)lipoprotein•19-kDalipoproteinfromM.tuberculosis,aswellassyntheticlipopeptides,inducedDCmaturation.TheresultingmatureDChadincreasedcellsurfaceexpressionofMHC-II,CD80,CD83,CD86,CD54,andCD58,suggestingthatthelipopeptidealoneissufficienttoinducematurationevents.•（MicrobialLipopeptidesStimulateDendriticCellMaturationViaToll-LikeReceptor2）PGNandLTADCmaturationisinducedbystimulifromGram-positivemicroorganisms,suchasPGNandLTA,withsimilarefficiencyasbyLPS.Finally,weprovideevidencethatTLR2andTLR4interactionwiththeappropriateligandisessentialforbacteria-inducedmaturationofDCs.TheRoleofToll-likeReceptors(TLRs)inBacteria-inducedMaturationofMurineDendriticCells(DCs)Poly(I:C)TreatmentofimmatureDCwithpoly(i:c)resultsinDCwithstableandhighexpressionofthecostimulatorymolecules,CD80andCD86,andexpressionofthematurationmarkerCD83.Accordingly,thephenotypicmaturationisaccompaniedbydown-regulationofpinocyticactivityandproductionofhighlevelsofIL-12andneglectableamountsofIL-10CTL.Polyriboinosinicpolyribocytidylicacid(poly(I:C))inducesstablematurationoffunctionallyactivehumandendriticcells.J.Immunol.163,57–61(1999).Choleratoxin(CT)CTinducesphenotypicandfunctionalmaturationofbloodmonocyte-derivedDC.Indeed,CT-treatedDCup-regulateexpressionofHLA-DRmolecules,B7.1andB7.2co-stimulatorymolecules,andareabletoprimenaiveCD4+CD45RA+Tcellsinvitro,drivingtheirpolarizationtowardstheTh2phenotype(CholeratoxininducesmaturationofhumandendriticcellsandlicencesthemforTh2priming.)Double-stranded(ds)RNAHumanDCsareactivatedbyinfluenzavirusinfectionandbydouble-stranded(ds)RNA.TheactivationresultsnotonlyinincreasedantigenpresentationandTcellstimulatorycapacity,butalsoinresistancetothecytopathiceffectofthevirus,mediatedbytheproductionoftypeIinterferon,andupregulationofMxA.Recognitionofdouble-strandedRNAandactivationofNF-kBbyToll-likereceptor3MechanismoftheactivationDCmaturationistypicallytriggeredbyproductsofmi-crobialorviralpathogens,suchasLPS,CpGDNA,ordsRNA.Formanyorallofthese,oneormoremembersofthefamilyofToll-likereceptors(TLRs)playacriticalrole.SubsetsofHumanDendriticCellPrecursorsExpressDifferentToll-likeReceptorsandRespondtoDifferentMicrobialAntigens