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CHAPTER3TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystemDominikSchenten*andRuslanMedzhitov*Contents1.Introduction882.DiverseSetsofPRRs892.1.TransmembranePRRs902.2.CytosolicPRR933.Cell-Type-SpecificPRRDistributionandtheInterplayBetweenPRRsinAdaptiveImmunity97þ4.InnateControlofCD4TCellResponses99þ4.1.Cell-autonomouscontrolofCD4Tcellresponses100þ4.2.IndirectcontrolofCD4Tcellresponses1015.BCell-IntrinsicControlofHumoralImmuneResponsesbyPRRs1066.PathologicalConsequencesofDefectivePRRSignalinginHumans1087.Conclusions110Acknowledgments111References112AbstractThemammalianimmunesystemcomprisesanadaptiveandaninnatecomponent.Theinnateimmunesystememploysalimitednumberofgerm-line-encodedpattern-recognitionreceptors(PRRs)thatrecognizeinvariantpathogen-associatedmolecularpatterns(PAMPs).Incontrast,theadaptiveimmunesystemdependsonthe*HowardHughesMedicalInstituteandDepartmentofImmunobiology,SchoolofMedicine,YaleUniversity,NewHaven,Connecticut,USAAdvancesinImmunology,Volume109#2011ElsevierInc.ISSN0065-2776,DOI:10.1016/B978-0-12-387664-5.00003-0Allrightsreserved.87 88DominikSchentenandRuslanMedzhitovgenerationofadiverserepertoireofantigenreceptorsonTandBlymphocytesandsubsequentactivationandclonalexpansionofcellscarryingtheappropriateantigen-specificreceptors.Inductionofadaptiveimmunitynotonlydependsondirectantigenrecognitionbytheantigenreceptorsbutalsoreliesonessentialsignalsthataredeliveredbytheinnateimmunesystem.Inrecentyears,wehavewitnessedthediscoveryofastillexpandingarrayofdifferentPRRsystemsthatgovernthegenerationofadaptiveimmunity.Here,wereviewourcurrentunderstandingofinnatecontrolofadaptiveimmunity.Inparticular,wediscusshowPRRsinitiateadaptiveimmuneresponsesingeneral,discussspecificmechanismsthatshapetheensuingTandBcellresponses,andhighlightopenquestionsthatarestillawaitinganswers.1.INTRODUCTIONDefenseagainstmicrobialassaultsisanessentialnecessityforalllivingorganisms.Consequently,alllifeformshaveevolvedstrategiesthataredesignedtolimittheinvasionofthehostbymicroorganisms.Plants,fungi,andlowermulticellularorganismsrelyonasetofstrategiesthatarecollectivelycalledinnateimmunity.Whiletheprecisecharacteristicsoftheinnateimmunesystemsdifferbetweenthevariousspecies,theyallshareseveralcentralfeatures.Innateimmunity,whichisgeneticallyfixedandthusinvariant,reliesonadefinedsetofreceptorsandisnonspecificasittargetswholeclassesofmicrobes.Theevolutionofvertebrateswasaccompaniedbytheemergenceofadaptiveimmunity.Bothjawedandjawlessvertebratesdevelopedimmunesystemsthatallowedforcombinatorialdiversitythroughtherearrangementofgerm-line-encodedgenesegmentsandthusenabledthedirecttargetingofspecificmicrobialinvaders(HerrinandCooper,2010;PancerandCooper,2006).Jawlessvertebratesbasedtheirimmunesystemonanancientreceptorcontainingleucine-richrepeats(LRRs),whichareacommonstructuralfeatureusedthroughoutinnateimmunityincludingmodernToll-likereceptors(TLRs)inmammals.Thus,boththelampreyandhagfish,theremainingjawlessvertebrates,diversifytwogerm-line-encodedLRR-containingreceptorsbyaddingadditionalLRR-encodinggenesegmentsthroughrecombination.Incontrast,jawedvertebratesevolvedmembersoftheimmunoglobulin(Ig)superfamilyfurther,whichledtotheadaptiveimmunesystemofmodernmammals.AllmammalsthereforegeneratecombinatorialdiversitythroughtheshufflingofgenesegmentsencodingIgdomains.Asaconsequenceofitsancestralhistory,themammalianimmunesystemconsistsoftwoparts:theinnateimmunesystemandtheadaptiveimmunesystem.Theinnateimmunesystem,whichemploysasmallsetof TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem89invariantpattern-recognitionreceptors(PRRs)thatrecognizepathogen-associatedmolecularpatterns(PAMPs),servesasafirstlineofdefensethatisrapidandremarkablyeffectiveinclearingmostinvadingpathogens.Incontrast,theadaptiveimmunesystem,whichselectivelyexpandsantigen-specificclonesfromanenormouspoolofTandBcellsharboringuniqueantigenreceptors,servesasasecondlineofdefensethatishighlyspecificandabletoformimmunologicalmemory.Thedeletionofself-reactiveTandBcellclonesduringthedevelopmentofthecellsformsthebasisforthediscriminationbetweenselfandnonselfbytheadaptiveimmunesystem.However,astheexistenceofthevariousautoimmunediseasesshows,clonaldeletionisanimperfectmechanism.Morethan2decadesago,CharlesA.JanewayJr.suggestedthattherecognitionofPAMPsbytheinnatesystemdeliversessentialsignalstotheadaptiveimmunesystemthatprovideanadditionallayerofself/nonselfdiscriminationandallowsforthedistinctionbetweeninnocuousandpathogenicantigens(Janeway,1989).Itisnowuniversallyrecognizedthatinnateinstructionofadaptiveimmunityisacriticalstepthatcontrolstheactivation,types,anddurationoftheadaptiveimmuneresponse.Innateinstructionoccursinitiallyduringtheinteractionbetweenantigen-presentingcells(APCs)andTcells.Whilethisinteractioniscriticalforthegenerationofanadaptiveimmuneresponse,itisclearthatinnateinstructionofadaptiveimmunityisaprocessthatoccursatmultiplestagesthroughouttheimmuneresponseandinvolvesallcelltypesparticipatinginaparticularresponse.Inthischapter,wewillprovideanoverviewofourcurrentunderstandingofinnateinstructionofadaptiveimmunity.Inaddition,wewillemphasizeaspectsthatinourviewarecurrentlyunderappreciatedanddeservemoreattention.2.DIVERSESETSOFPRRSWhileallPRRsareabletodetectmicrobesandinduceinnateimmuneresponses,theycannonethelessbeclassifiedintodistinctfunctionalclassesthatservedifferentpurposes.Thefirstclass,consistingofsecretedPRRssuchasmannose-bindinglectin(MBL),isinvolvedinopsonizationandcomplementactivation.Thesecondclassconsistsofreceptorsthatinducephagocytosisondendriticcells(DCs)andmacrophagessuchasthescavengerreceptorormannose-bindingreceptor(MR).TheyfacilitatetheuptakeofmicrobesintothephagosomeandtheprocessingoftheforeignproteinsintoantigenicpeptidesforTcellstimulation.ThethirdclassconstitutesagroupofPRRsthatinducetheproductionofantimicrobialpeptides,chemokines,andproinflammatorycytokines.Importantly,thesePRRsupregulatecostimulatorymoleculesandtrigger 90DominikSchentenandRuslanMedzhitovthesecretionofcytokinesthatareessentialforthegenerationoftheadaptiveimmuneresponse.Basedontheircellularlocalization,thelatterclassofPRRscanbefurtherdividedintoPRRsthatmonitortheextracellularmilieu(TLRsandsomeC-typelectins)andPRRsthatdetectintracellularinfections(RIG-I-likereceptors,NOD-likereceptors(NLRs),andDNAsensors).Forthepurposeofthischapter,wewillrestrictourdiscussiontoPRRsthatareabletoinduceanadaptiveimmuneresponse.2.1.TransmembranePRRsTransmembranePRRscanbelocatedeitheronthecellularsurfaceorinsidephagosomesandendosomes.Theycomprisetwofamilies,TLRsandasubgroupofC-typelectins,whichrecognizedistinctPAMPsandusedistinctsignalingpathways.2.1.1.Toll-likereceptorsTLRsarebyfarthebest-studiedclassofPRRs.Manyoftheirligandsareknown,asaretheirsignalingpathwaysandthephysiologicalconsequencesoftheiractivation.TLRsowetheirprominenceinparttothefactthattheywerethefirstfamilyofPRRsthatwasdiscovered.However,theyalsoserveasaparadigmfortheinnatecontrolofadaptiveimmunity.TLRsaresufficientfortheinductionofadaptiveimmuneresponsesandcontrolthematmultiplelevelsthatincludetheinduction,þþdifferentiation,andmemoryformationofbothCD4andCD8Tcellsandthegenerationofantibodyresponses.TheTLRfamilyconsistsofatleast13membersinmammals.Threeofthesereceptors(TLR3,TLR7,andTLR9)resideinendosomeswheretheyrecognizenucleicacids.TheremainingTLRsarelocatedonthecellmembraneandareactivatedbyadiverserangeofPAMPsthatincludeLPS,bacteriallipoproteins,zymosan,andflagellin(Alexopoulouetal.,2001;Hemmietal.,2000;Hoshinoetal.,1999;Poltoraketal.,1998;Qureshietal.,1999).AllTLRsaretypeItransmembraneglycoproteinsandcontainacytosolicdomainknownastheToll/IL-1R(TIR)domainthatshareshomologywiththeinterleukin-1receptor(IL-1R;Dunneetal.,2003).AtleastfouradaptormoleculesareinvolvedinthesignaltransductionofTLRs(Akira,2004).MyD88isthecentralsignalingadaptorformostTLRsandreceptorsofIL-1familymembers.Inaddition,MyD88hasalsobeenshowntoassociatewiththeIFN-greceptorandTACI,althoughthemechanismsoftheseinteractionsarelessclear(Heetal.,2010;SunandDing,2006).TheTIRdomainofMyD88associateswiththeTIRdomainofTLRs(andIL-1R),whichleadstotherecruitmentandphosphorylationofIRAK-4andIRAK-1(Adachietal.,1998;Burnsetal.,1998;Kawaietal.,1999;Lietal.,2002;Medzhitovetal.,1998;Suzukietal.,2002;Swanteketal.,2000;Wescheetal.,1997).Theactivatedkinasespromotethebinding TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem91ofTRAF6,andthisinteractionresultsultimatelyintheexpressionofNF-kB-dependentinflammatorycytokinessuchasTNFa,IL-1,andIL-6.MostTLRsrelyonMyD88astheessentialsignalingadaptorfortheinductionofproinflammatorycytokines,whileTLR3doesnotuseMyD88anddependsontheadaptorTRIFtoinducethesecytokines.TLR4andtheendosomalTLRscanalsoinducetypeIinterferons.TLR7andTLR9inducethetypeIinterferonresponseviaMyD88andIRF7.Incontrast,TLR3andTLR4(viaTRAM)relyonTRIF,whichmediatestheactivationofinterferonregulatoryfactor3(IRF3)inordertoinducetheexpressionoftypeIinterferons(Hoebe,2003;Kawaietal.,2001;Yamamotoetal.,2003).ActivationofTLRsignalinginAPCsresultsincytokineproductionandtheupregulationofcostimulatorymoleculesthatarenecessaryfortheinductionofTcellresponses.TheoriginaltheoriesofinnatecontrolofadaptiveimmunitypostulatedadependenceoftheupregulationofcostimulatorymoleculesonPRRactivation,butthepicturehasbecomemorecomplicatedinrecentyears.Indeed,professionalAPCssuchasDCsalreadyexpresshighlevelsofcostimulatorymoleculesandyet,intheabsenceofPAMPs,antigenpresentationbytheseAPCsleadstotoleranceratherthanimmunity.Further,inflammatorymediators,suchasTNFa,canalsoactivateDCsandinducetheupregulationofcostimu-þlatorymolecules.TheseDCscansupporttheexpansionofCD4Tcellbutfailtoinducetheirdifferentiationintoeffectorcells(SporriandReiseSousa,2005).DespiteconsiderableeffortstounderstandtherulesgoverningactivationofTcells,andtherelativeroleofcostimulatorymoleculesandcytokinesinthisprocess,theidentitiesofallthesignalsthatarenecessaryandsufficientforTcellactivationremainpoorlyunderstood.Itappearstobeclear,though,thatcostimulationaloneisnecessarybutinsufficientforTcellactivationwhileTLR-drivenactivationofAPCsissufficienttoprovideallsignalsnecessaryfortheinductionofTcellresponses.AllTLRscaninduceaTH1response.Inaddition,manybutnotallTLRscanalsoinduceaTH17response.PAMPsareessentialformarkingproteinantigensasforeignandtheirrecognitionbyPRRsthusprovidesalayerofselfversusnonselfdiscriminationinadditiontotheclonalselectionoflymphocytes.ThephysicalassociationofPAMPswithantigensensuresthattheantigenandPAMPsendupinthesameendosomeoftheAPCandenablesthecelltopreferentiallypresenttheforeignantigensaspeptideMHCclassIIcomplexesonthecellsurface(BlanderandMedzhitov,2004).WhileTLRshavebeenshowntobenecessaryandsufficientfortheinductionofTcellresponsesinimmunizationsusingTLRsasadjuvantandinthecaseofvariousinfections,itshouldbenotedthattherequire-mentforinnateinstructionofadaptiveimmunityisnotimpervioustotheunintendedeffectsofartificialexperimentalsystems.Inparticular,we 92DominikSchentenandRuslanMedzhitovhavefoundthatTLRsignalingisnotrequiredwhenTcellprecursorfrequenciesareartificiallyinflatedthroughtheuseofTCR-transgenicTþcells.CD4Tcellscarryinganovalbumin-specificTCRtransgenearestillabletomountavigorousimmuneresponsetoanotherwiseTLR-depen-dentimmunizationaftertransferintoMyD88-deficientmice.SimilarþobservationsweremadewithTCR-transgenicCD4TcellsdeficientoftheIL-6receptorachain(NoahPalm,SimoneNish,DominikSchenten,RuslanMedzhitov,unpublished).Thus,certainexperimentalmanipula-tionscanalteroreliminatetherequirementsforinnateimmunesignals,whichcanaffecttheinterpretationoftheresults.2.1.2.C-typelectinsDectin-1,Dectin-2,andMinclearemembersofagrowingfamilyofC-typelectinsthatareexpressedbyDCsandmacrophagesandareinvolvedintheinductionofadaptiveimmunity(KerriganandBrown,2010).WhileDectin-1wasinitiallydescribedasareceptorthatrecognizesanunknownendogenousligand,itisnowmainlyrecognizedasaPRRthatisactivatedbyb-(1,3)-glucanssuchaszymosan.Theseglucansareamajorcomponentoffungalcellwalls,andconsequently,Dectin-1ismostprominentlyrecognizedasaPRRthatisspecializedonthedetectionoffungalspeciessuchasPneumocystiscariniiorCandidaalbicans(Tayloretal.,2007).However,Dectin-1canalsodetectanumberofmycobacterialspecies,eventhoughb-glucansareabsentfrommycobacteriaandtheligandsmediatingthisrecognitionhavesofarremainedelusive(Leeetal.,2009;Rothfuchsetal.,2007;Shinetal.,2008;YadavandSchorey,2006).Dectin-2isalsoaPRRthatdetectscomponentsoffungalcellwalls.However,itrecognizesa-mannansandisthereforeabletodetectfungalhyphae,whileDectin-1cannot.Indeed,Dectin-2deficiencyrendersmicehighlysusceptibletoinfectionswithseveralstrainsofC.albicans,whileDectin-1-deficientanimalsonlysuccumbtotheseinfectionsinastrain-specificmanner(Bietal.,2010;Saijoetal.,2007,2010;Tayloretal.,2007).RecentstudiesalsoshowedthatMincleisanotherC-typelectininvolvedinthedetectionoffungalPAMPs,althoughtheexactnatureoftheligandhasnotbeenidentifiedsofar(Yamasakietal.,2009).Inaddition,Minclealsorecognizesmycobacterialcordfactoraswellasnecroticcells(Ishikawaetal.,2009;MatsunagaandMoody,2009;Schoenenetal.,2010;Yamasakietal.,2008).ReceptorsignalingoftheseC-typelectinsisquitedifferentfromthatofTLRsandismorecloselyrelatedtothatofantigenreceptorsinlymphocytes.Whilethedetailsoftheirsignalingpathwaysdifferdependingontheparticularreceptorandcelltype(Goodridgeetal.,2009),theyallcontainanoncanonicalITAMmotifthatrecruitsthetyrosinekinaseSykasanessentialsignalingadaptor.FollowingtheactivationofDectin-1inDCs,Sykthenleadstotherecruitmentof TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem93CARD9andthesubsequentactivationofNF-kBviatheBcl10/Malt1complex.Asaresult,theactivationofDectin-1leadstotheproductionofproinflammatorycytokinesandchemokines,includingIL-1,IL-6,and2þCCL3.Inaddition,SykalsoactivatesMAPKandmobilizesCathatactivatesNFAT,whichresultsintheproductionofadditionalcytokinesincludingIL-23(Gringhuisetal.,2009).BothDectin-2andMinclearethoughttoinduceasimilarsetofsignalingmolecules.However,thedetailedconsequenceoftheactivationofthesereceptorsisstillawaitingfurtherinvestigation.LikeTLRs,activationofC-typelectinsissufficientfortheinductionofadaptiveimmunity.AsDectin-1inducesIL-23butnotIL-12,ithasbeenlinkedmorecloselytotheinductionofTH17responses,althoughitappearstobealsoinvolvedinthegenerationofTH1responsestomycobacteria(Acosta-Rodriguezetal.,2007b;LeibundGut-Landmannetal.,2007;Zenaroetal.,2009).TH17cellsarethoughttodirectimmuneresponseagainstextracellularmicrobessuchasfungi,inpartbyrecruitingneutrophilsthatkillthemicrobesbyphagocytosis,releaseofantimicrobialpeptides,andneutrophilextracellulartraps(NETs).Inthiscontext,itisthereforestillrathermysteriousthatintracellularmycobacteriaarealsopotentactivatorsofDectin-1.2.2.CytosolicPRRTheextracellulararrayofPRRsiscomplementedbycytosolicreceptors,someofwhichcanalsoinitiateadaptiveimmuneresponsesuponinfectionofthecellbybothcytosolicbacteriaandviruses.Thereceptorsfallintoatleastthreeclasses,namelyRIG-Iikereceptors(RLRs),DNAsensors,andNLRs.2.2.1.RIG-I-likereceptorsRIG-IandMDA5arebothwidelyexpressedcytosolicRNAhelicasesthatareactivatedbyRNAvirusesandrecognizethe50-triphosphatemoietyandhigher-orderstructuresofdsRNA,respectively(Pichlmairetal.,2009;Schleeetal.,2009).StimulationofRIG-IandMDA5resultsinthebindingoftheRLRstothesignalingadaptorMAVS,whichleadstotheactivationofNF-kBandtheinductionofaTBK1andIRF3-mediatedtypeIinterferonresponse.Interestingly,MAVSlocalizestobothperoxisomesandmitochondria,resultinginthefastandtypeIinterferon-independentexpressionofantiviralgenesbytheformerpoolofMAVSandthedelayedandtypeIinterferon-dependentexpressionofantiviralgenesbythelatterpoolofMAVS(Dixitetal.,2010).Moreover,RIG-IcanalsotriggeranMAVS-independentpathwaythatinvolvesthesignalingadaptorASCindependentlyofNLRP3andleadstotheproductionofIL-1bbycaspase-1(seebelow;Poecketal.,2010). 94DominikSchentenandRuslanMedzhitovInadditiontodsRNAviruses,forexample,Reovirus,RIG-IandMDA5alsorecognizessRNAvirusesthatproducedsRNAduringtheirlifecycle(Looetal.,2008).Thus,somessRNAvirusesproduceagonistsforbothRIG-IandMDA5(DengueandWestNilevirus),whileothersactivateeitherRIG-I(VesicularStomatitisVirus(VSV),RespiratorySyn-cytialVirus(RSV),HepatitisCVirus(HCV),andInfluenza)orMDA5(Poliovirus;Katoetal.,2005,2006;Looetal.,2008;Saitoetal.,2008).Recently,anothernucleicacid-detectingreceptorhasbeenidentified,calledLRRFIP1(Yangetal.,2010).ThisreceptorisnotanRLR,butisstillstimulatedbytheRNAofVSV.LRRFIP1activatesb-catenininordertoinduceIFN-b.Asb-cateninismorecommonlyknowntoactasacofactorintheWntsignalingpathwayandthereforethoughttoregulatecellularfunctionslikeproliferation,differentiation,andadhesion,itisratherunusualtofinditinaninflammatorycontext.However,thisproteinhasalsobeensuggestedtonegativelyregulateNF-kB-driveninflammationinbacterialinfections(Duanetal.,2007).Thus,b-cateninmayplayabroaderroleintheregulationofinnateimmunitythaninitiallyanticipated.2.2.2.DNA-sensingreceptorsThecytosolicDNAofsomevirusesandbacteriasuchasherpessimplexvirus1(HSV-1),vacciniavirus(VV),adenovirus,andLegionellaisnotsenseddirectlybutinducesatypeIinterferonresponsethroughtheRIG-I/MDA5pathwaybygeneratingdsRNAintermediatesfromAT-richDNAupontranscriptionbyRNApolymeraseIII(Ablasseretal.,2009;Chiuetal.,2009;Delaloyeetal.,2009).Inadditiontotheseindirectmeansofdetection,severalbonafideDNAsensorshavealsobeenpostulated.OneofthesefactorsisDAI,whichsensestheZformofdsDNAandtriggersatypeIinterferonresponseviaIRF3.WhileDAIcanrespondtohumancytomegalovirus(CMV),DAI-deficientmicearestillcapabletomountatypeIinterferonresponsetoexogenousB-DNA,suggestingtheexistenceofadditionalfactorsthatsensecytosolicDNA.Interestingly,LRRFIP1canalsosenseboththeBandZformsofDNAinadditiontoRNAandthuspresentsanalternativepathwayfortheactivationofatypeIinterferonresponse.Indeed,cellswithreducedlevelsofLRRFIP1exhibitasignificantlyreducedinductionofIFN-buponinfectionwithListeriamonocytogenes(Yangetal.,2010).Recently,thehumanproteinIFI16anditsmurineorthologp204havealsobeenimplicatedinthecytosolicrecogni-tionofDNA(Unterholzneretal.,2010).ActivationofIFI16viaitsHINdomainappearstoinducebothNF-kBandIFN-bupontheintroductionofexogenousDNAintothecytosolorinfectionwithHSV-1.ThisfeatureseemstoseparateIFI16fromtherelatedproteinAIM2,whichisinvolvedintheactivationofcaspase-1butnottheinductionofIFN-b(seebelow).Finally,itisinterestingtonotethatcytosolicDNAcanalsobederivedfromendogenoussources.ThelevelofendogenouscytosolicDNAis TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem95usuallykeptlowbynucleasessuchasTrex1.However,thefailureofthismechanismcanleadtotheaccumulationoftheligandsandcauseinter-feron-drivenautoimmunediseases(Stetsonetal.,2008).2.2.3.NOD-likereceptorsNLRsformalargegroupofwidelyexpressedintracellularreceptorsthatarecharacterizedbyanLRRdomainthoughttoberesponsibleforligandbinding(eventhoughdirectbindingofaligandtoanNLRhasnotbeenshownsofar)andoneoffourN-terminaldomainsthatmedi-atetheactivationofdownstreamtargets.Withrespecttothecontrolofadaptiveimmunity,thebest-knownNLRsaretheCARD-domaincon-tainingNLRC1andNLRC2(NOD1andNOD2).NLRC1andNLRC2areactivatedbyg-D-glutamyl-meso-diaminopimelicacid(meso-DAP)andmuramyldipeptide(MDP),respectively,whicharederivedfromthebacterialcellwallcomponentpeptidoglycan(PGN).ThemodebywhichtheligandsgainaccesstotheintracellularNLRC1andNLRC2isnotwelldefined.IntracellularbacterialikeL.monocytogenesareknowntoescapeintocytosol,whereasMDPandmeso-DAPfromextra-cellularbacteriaseemtobetakenupbyendocytosisandthentrans-portedintothecytosolviathetransportersPepT1andPepT2(Ismairetal.,2006;Swaanetal.,2008).Uponstimulation,bothNLRC1andNLRC2recruitRIP2,whichinturnresultsintheactivationofMAPKandNF-kBandsubsequentproductionofinflammatorycytokinesandcostimulatorymolecules(inDCsandmacrophages;Todateetal.,2001).Inaddition,NOD2canalsoinducetypeIinterferoninresponsetoviralinfectionsbyactivatingtheMAVSpathway(Sabbahetal.,2009).Conse-quently,NLRC1andNLRC2havebeenshowntopromoteTH1andTH17responsesandantigen-specificantibodyresponses(Fritzetal.,2007;Kobayashietal.,2005;Shawetal.,2009;vanBeelenetal.,2007).SomeNLRscanformlargemultimericcomplexes,termedinflammasomes,whicharenecessaryfortheactivationofcaspase-1(SchroderandTschopp,2010).Caspase-1activation,inturn,isrequiredforthecleavageofpro-IL-1bandpro-IL-18inordertogenerateandsecreteIL-1bandIL-18.ThesecretionofactiveIL-1bandIL-18thereforeappearstoberegulatedatthelevelofposttranslationalprocessing,whilethetranscriptionalactivationofpro-IL-1bandpro-IL-18dependsonproinflammatorystimulisuchasLPS.Severaldistinctinflamma-someshavebeenidentifiedandaredefinedbytheNLRproteincontainedinthecomplex:TheNLRC4,NLRP1,andNLRP3inflamma-some(alsocalledIPAF,NALP1,andNALP3inflammasome,respec-tively).Followingactivation,theNLRP1andNLRP3inflammasomesactivatecaspase-1viatheadaptorproteinASC,whiletheNLRC4inflammasomecanactivatecaspase-1directly(althoughNLRC4mayalsorequireASCinsomecases).Bacterialproducts,suchasflagellin 96DominikSchentenandRuslanMedzhitovandanthraxlethaltoxin,stimulateNLRC4andNLRP1.Incontrast,theactivationofNLRP3appearstobemorecomplex.Therangeofstimuliinvolvesmicrobialproducts,pore-formingtoxins,inorganiccrystals,andextracellularATP(Dostertetal.,2008;Eisenbarthetal.,2008;Hornungetal.,2008;Ichinoheetal.,2009;Kahlenbergetal.,2005;Mariathasanetal.,2006;Muruveetal.,2008;Shietal.,2003).ItisthereforeassumedthatNLRP3doesnotsensethesestimulidirectlybutinsteadrespondstocellularabnormalitiesresultingfromthesesti-muli,suchasmembranedamagecausedbyinorganiccrystals.Theeffluxofpotassiummaybeanimportantintermediatestepinthisprocess,asATPtriggersthereleaseofpotassiumthroughthepurinergicionchannelP2X7receptorandtheotherclassesofstimulimightcauseasimilareffluxofpotassium(Ferrarietal.,2006;Kahlenbergetal.,2005).OneconsequenceofP2X7activationmaybetheopeningofthepan-nexin-1pore,whichallowstheentryofmicrobialproductssuchasMDPintothecytosol(Kannegantietal.,2007;Marina-Garciaetal.,2008;PelegrinandSurprenant,2006;Pelegrinetal.,2008).However,othermodelsexplaininginflammasomeactivationhavealsobeenputforwardandincludethegenerationofreactiveoxygenspeciesorthedisruptionofthelysosomeandreleaseofitsmicrobialcontents(Dostertetal.,2008;Hornungetal.,2008;Sharpetal.,2009).Recently,anotherinflammasomehasbeendescribedthatisdefinedbythePRRAIM2(Burckstummeretal.,2009;Fernandes-Alnemrietal.,2009;Hornungetal.,2009;Robertsetal.,2009).WhileAIM2doesnotbelongtotheNLRfamily,itstillreliesonASCinordertoactivatecaspase-1.AIM2respondstodsDNAandthereforehasbeenimplicatedinthesensingofDNAviruseslikeVVandmouseCMVaswellasthebacteriaFrancisellatularensisandL.monocytogenes(Fernandes-Alnemrietal.,2010;Rathinametal.,2010;Saueretal.,2010;Warrenetal.,2010).Interestingly,thelattermicrobe,whichisalsosensedbytheNLRP3inflammasome,needstheexpressionofthepore-formingtoxinLLOforinflammasomestimulation,indicatingthattheescapefromthelysomesisanessentialstepintheactivationprocessofeitherNLRP3orAIM2bythismicrobe(Kimetal.,2010;Meixenbergeretal.,2010).AnimportantfeatureofNLRP3(andAIM2)inflammasomeactivationistherequirementofanadditionalsignalthatisdeliveredbyLPSandothermicrobialstimuliorevenTNFaandothercytokinesthatactivateNF-kB.ItthereforeappearsthattheNLRP3inflammasomeisnotabletobeactivatedwithoutaprimingsignalfromanotherPRRandthereforeisunlikelytoinduceadaptiveimmuneresponsesonitsown.Nonetheless,IL-1bandIL-18areimportantcytokinesfortheinstructionofTcellresponsesandthusinflammasomesplayanimpor-tantroleintheinnateinstructionofadaptiveimmunity. TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem973.CELL-TYPE-SPECIFICPRRDISTRIBUTIONANDTHEINTERPLAYBETWEENPRRSINADAPTIVEIMMUNITYUnlikereceptorsoftheadaptiveimmunesystem,PRRsarebroadlyexpressedacrossmultiplemigratoryandnonmigratorycelltypes.Allthesecelltypescanthereforedetectthepresenceofinfectionandcantheoreticallycontributetoinnatecontrolofadaptiveimmunity.ElucidatingtherelativecontributionsofthevariouscelltypesthatcandetectinfectionthroughPRRsisandwillcontinuetobeachallengingtasksincesomanycelltypescanrespondtothepresenceofinfectioninsomanydifferent,yetoftenpartiallyoverlapping,ways.Inexperimentalsettings,itispossibletocreatesituationsthattargetindividualPRRsandstudiesthatspecificallyaddressthefunctionsofindividualPRRshavecontributedtremendouslytotheunderstandingofinnateinstructionofadaptiveimmunity.However,suchconditionsneveroccurinreal-lifescenarios.InfectiousmicroorganismscontainligandsformultipledifferentclassesofPRRs,cantriggerthesamePRRinmultipledifferentcelltypessimultaneously,andhaveaccesstovariouscellularcompartments,allofwhichresultsintheactivationofmultipleclassesofPRRsduringactualinfections.Moreover,simultaneousinfectionbydiffer-entmicrobescanfundamentallyaltertheoutcomeoftheinfections(Bartonetal.,2007;Gumenscheimeretal.,2007;Humphreysetal.,2008;Jamiesonetal.,2010;Navarinietal.,2006).Consequently,aunifyingandsystematicinsightintotheinteractionbetweenmultiplePRRsisstilllacking.WhileanygivenclassofPRRsutilizesthesamebasicsignalingmachinery,itcanstilltriggerdistinctresponsesdependingonthecelltypethatisactivated,theligandthatisrecognized,andtherecenthistoryoftheparticularrespondingcell.ForTLRs,whichcanexhibitaparticularlybroadrangeofresponses,thisdistinctionisaidedbytheuseofdifferentsignalingadaptors.BothTLR2andTLR4employMyD88inordertoinduceproinflammatorycytokineswhileTLR4alsorecruitsTRIFinordertoinducetypeIinterferons.Inaddition,someTLRsinducedistinctresponsesusingthesamesignalingadaptor.BothTLR7andTLR9induceaMyD88-dependenttypeIinterferonresponsesinplasmacytoidDCs(pDC),whilethestimulationoftheseTLRsinothercelltypesdoesnotinduceatypeIinterferonresponse(Gillietetal.,2008).Moreover,B-typeCpGDNAinducesonlyproinflammatorycytokinesinpDCs,whereasA-typeCpGDNAalsoresultsintheproductionoftypeIinterferon.AnanalogousdifferencehasalsobeenobservedrecentlyforTLR2,whichcaninduceaMyD88-dependenttypeIinterferonresponseininflammatorymonocytesbutnotinothermyeloidcells(Barbalatetal.,2009).Interestingly,theabilityofTLR2totriggeratypeIinterferonresponseintheformercelltypedependsontheparticularligand. 98DominikSchentenandRuslanMedzhitovVVinducessucharesponsewhilePam3CSK4doesnot.Themechanismsunderlyingthisdistinctionarenotwellunderstood.However,thesignaltriggeringthereleaseofproinflammatorycytokinesisgeneratedbyplasmamembrane-associatedMyD88,whiletheinductionofatypeIinterferonresponseoriginatesfromanendosomalpoolofMyD88(Barbalatetal.,2009).Thelatteraspectseemstobeacommonfeatureofalltypelinterferon-inducingTLRsincludingTLR4,whichinducesproinflammatorycytokinesviatheplasmamembrane-associatedMyD88andtypeIinterferonviatheendosomalTRIF(Kaganetal.,2008).InadditiontoitseffectsinpDCs,VVcanalsoinducetypeIinterferonsinothermyeloidcells.However,inthesecellsTLR2inducesonlyproinflammatorycytokineswhilethetypeIinterferonresponseisdependentonMDA5(Delaloyeetal.,2009;Zhuetal.,2007).TherelativecontributionsofTLRversusRLRactivationtothetypeIinterferonresponseandinductionofadaptiveimmunityhasbeenstudiedinexperimentalsettingsthatincludebothimmunizationsandviralinfec-tions.Poly:ICisrecognizedbybothTLR3andMDA5.Proteinimmuniza-tionsusingpoly:ICasadjuvantrevealedthattheMAVSsignalingpathwayisrequiredfortheinductionofantibodyresponses,whiletheTRIFpathwayisnotrequired(Kumaretal.,2008).Nonetheless,theTRIFpathwaycontributestothegenerationoftheantibodyresponse,asitisevenmoredefectiveinMAVS/TRIF-deficientcompoundmutantmice.þThetwosignalingpathwaysalsocooperateintheinductionofbothCD4þandCD8Tcellresponses,whicharereducedinmicedefectiveinTLR3orMDA5signalingandcompletelyabrogatedinMAVS/TRIF-deficientcompoundmutantmice(Kumaretal.,2008;Trumpfhelleretal.,2008).Thesefindingsareincontrasttotheobservationsmadefortheadaptiveimmuneresponsesagainstlymphoidchoriomeningitisvirus(LCMV)andInfluenzavirus.InLCMV,MAVS-mediatedsignalingcontributestothesecretionofIFN-a.However,MyD88-dependentsignalingisthemajordriveroftheadaptiveimmuneresponse.TheserumlevelsofbothtypeIinterferonsandproinflammatorycytokinesarestronglyreducedinMyD88-deficientmice,mostlikelyduetotheactivationofTLRsinpDCs(Jungetal.,2008).Consequently,MyD88butnotMAVSisrequiredþfortheinductionsofaCD8TcellresponseagainstLCMV.Similarly,bothpathwaysalsocontributetotheinductionoftypeIinterferonsuponinfectionwithInfluenzavirus.TheresponseiscompletelydefectiveinMyD88/MAVS-deficientcompoundmutantmice(Koyamaetal.,2007).þHowever,theinductionofaCD4TcellresponseaswellastheantibodyresponsedependsonMyD88signalingbutnotMAVSsignaling.Interest-þingly,theCD8TcellresponserequiredneitherMyD88norMAVS,suggestingeitherredundancybetweenthetwopathwaysinthisregardortheinvolvementofadditionalPRRs.CooperationbetweentheMyD88andMAVSpathwayshasalsobeenimplicatedinthegenerationof TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem99adaptiveimmunityinresponsetoinfectionwithRSV.WhilethetypeIinterferonresponseinRSVinfectionsdependsentirelyonMAVSsignal-ing,bothMyD88andMAVSareinvolvedintheclearanceofthevirus.ThetwopathwaysalsosynergisticallycontributetothegenerationofantibodyresponsesbutneitherMyD88norMAVSisrequiredfortheþinductionofCD8Tcellresponses(Bhojetal.,2008).Interestingly,though,NOD2signalingviaMAVShasbeenidentifiedasacriticalfactorinthegenerationofprotectiveimmunitytoRSV(Sabbahetal.,2009).Together,theseexamplesshowthatwhilePRRscanoperateinisolationinsomeexperimentalsettings,theymorecommonlyactincollaborationtocontrolinfections,althoughtherelativecontributionsofindividualPRRstotheinstructionofadaptiveimmunitycanvarygreatlyanddependsonthespecificinfection.AsimilarcooperationbetweendifferentclassesofPRRshasalsobeenobservedforC-typelectinssuchasDectin-1andTLRsinordertoachieveamaximalinductionoftheadaptiveimmuneresponse.WhiletheactivationofDectin-1aloneissufficienttoinstructanadaptiveimmuneresponse,Dectin-1alsosynergizeswithseveralTLRstosignaltheproductionofproinflammatorycytokinesincludingTNFainresponsetobothfungalandbacterialinfections(Dennehyetal.,2008;Ferwerdaetal.,2008;Leeetal.,2009;Neteaetal.,2006;Shinetal.,2008;YadavandSchorey,2006).Importantly,theinteractionbetweenDectin-1andTLRssignalingcanalsoaltertheadaptiveimmuneresponsequalitativelyasithasbeenimplicatedinshiftingthebalancebetweentheIL-12-dependentTH1andtheIL-23-dependentTH17responseinfungalinfections(Dennehyetal.,2009;Gerosaetal.,2008).CoactivationofthesepathwaysinDCsandmacrophagestriggerstheproductionofIL-6,IL-10,andIL-23,andsuppressesproductionofIL-12ascomparedtoTLRactivationalone(Dennehyetal.,2009).Itisnotentirelyclearhowthisinteractionisregulatedonthemolecularlevel,althoughbothSykandMyD88arenecessary(Dennehyetal.,2008,2009).þ4.INNATECONTROLOFCD4TCELLRESPONSESTheactivationofPRRsresultsintheupregulationofcostimulatorymoleculesandthesecretionofmanycytokinesbytheAPCs,ofwhichmultipleareinvolvedintheinstructionofTcellresponses.Inadditiontotheseindirectmeansofcontrol,TcellsalsoexpressanumberofPRRsthemselves,suggestingthatPRRsmayshapetheensuingTcellresponsedirectlyuponencounteroftheappropriatePAMPs.WewillfirstdiscussþtheCD4Tcell-intrinsicfunctionofPRRactivationandwillthenreviewþtheroleofcytokinesinthecontrolofCD4TcellresponseswithaparticularemphasisontheeffectsofIL-1andIL-6. 100DominikSchentenandRuslanMedzhitovþ4.1.Cell-autonomouscontrolofCD4TcellresponsesþCD4TcellsexpressseveralclassesofPRRs.BothmurineandhumanþCD4TcellsexpressmostTLRs,eventhoughdifferentstudieshavecometovaryingconclusionsabouttheprecisepatternoftheTLRsexpressedinþparticularCD4Tcellsubsetsoractivationstates.InvitrostudiesshowedthatstimulationofTcellswithsomeTLRligands(inparticular,TLR2andTLR9agonists)hascostimulatoryeffectsthatleadtoenhancedprolifera-þtionandsecretionofIL-2.ExposureofCD4TcellstoCpGDNAalsoþinducesBCLXL,suggestingthattheactivationofTLRsinCD4Tcellsenhancessurvivalundersomeconditions(Gelmanetal.,2004).Interest-ingly,undertheseconditions,MyD88notonlyactivatesNF-kBbutalsoassociateswithPI3KinordertophosphorylateAktandGSK-3(Gelmanetal.,2006).ThelatterpathwayinducesIL-2productionandproliferation,whiletheformerpathwayprovidessurvivalsignals.InadditiontotheirþroleinfacilitatingtheproliferationandsurvivalofCD4effectorTcells,þþTLRscanalsoinfluenceCD4CD25regulatoryTcells(Tregs)directlybydampeningtheirsuppressivecapabilities(LaRosaetal.,2007).ActivationofbothTLR2andTLR9leadstotheexpansionofTregs.However,inthepresenceofTLRligands,TregstransientlyexpresslowerlevelsofFoxP3andlosetheirabilitytosuppresseffectorTcellsandregainthisfunctiononceTLRstimulationceases(Liuetal.,2006;Sutmulleretal.,2006).Thus,þsomeTLRsseemtostimulatebothCD4effectorTcellsandsuppressTregsconcurrentlyinordertopromotetheexpansionoftheeffectorTcellpopulation.However,thisconclusionisbasedmostlyonresultsfrominvitroexperimentsandatthepresenttime,itisuncleartowhatextentthesefindingstranslateintoinvivosituations.ThedirectcontributionofþTLRsignalingtoCD4TcellresponsesinvivohasbeenmostlyanalyzedusingMyD88-deficientmice.BonemarrowchimeraswithaMyD88-defi-cientTcellcompartmentdisplayadecreasedabilitytogenerateaTH1responsetoToxoplasmagondii,resultinginanincreasedlethalitythatwascomparabletothatofMyD88-deficientmice(LaRosaetal.,2008;Scangaþetal.,2002).Likewise,MyD88-deficientnaı¨veCD4TcellsfailtoinducecolitisfollowingtheirtransferintoRag2-deficientmice,whereaswild-typeTcellscausedisease(Fukataetal.,2008;Tomitaetal.,2008).Moreover,whenbothcelltypesarecotransferred,MyD88-deficientTcellsdonotexpandaseffectivelyaswild-typecontrolcells.Tcell-intrinsicMyD88signalingisalsoimportantfortheinductionofantibodyresponsesbyþþCD4TcellsaswellasthecontrolofLCMVinfectionsbyCD8Tcells(Gelmanetal.,2006;Rahmanetal.,2008).ThesefindingsarethereforeconsistentwiththenotionofadirectTLR-mediatedcontrolofTcellresponses.However,asthesestudiesmainlyemployedMyD88-deficientTcellsratherthanTLR-deficientTcells,itisimportanttokeepinmindthattheseobservationsmayinsteadbeattributabletodefectivesignalingof TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem101IL-1familymembersinthesecells(seenextsection).Indeed,bonemarrowchimeraswithaTcellcompartmentlackingspecificTLRswereallasresistanttoT.gondiiinfectionaswild-typemice,suggestingthatthedefectcannotbepinpointedtoasingleTLR(Debierre-Grockiegoetal.,2007;Hitzigeretal.,2005;Minnsetal.,2006;Scangaetal.,2002).Nonetheless,arecentstudydemonstratedthatmicewithaTLR2-deficientTcellcompart-mentgeneratedweakerTH17responsesandweremoreresistanttoexper-imentalautoimmuneencephalomyelitis(EAE;Reynoldsetal.,2010).ThisstudyshowedclearlythatdirectTcell-intrinsicTLR2activationcanposi-tivelyinfluencethecourseoftheTcellresponse,atleastundersomeconditions.BesidesTLRs,TcellsalsoexpressRLRsandNLRs.NOD2-deficientmicearehighlysusceptibletoinfectionswithT.gondii,eventhoughthispathogenisdevoidoftheNOD2ligandMDP(Shawetal.,2009),suggestingtheexistenceofadditionalNOD2ligands.Importantly,NOD2-deficiencyresultsinanimpairmentofIFNgsecretionandthisdefectcanbetracedtoTcell-intrinsicrequirementforNOD2togenerateaTH1response.Moreover,NOD2-deficientTcellsareunabletoinducecolitisupontransferintolymphopenichosts(Shawetal.,2009).ThisdefectisassociatedwithdefectiveproductionofIL-2bytheNOD2-deficientTcells,whichisreminiscentoftheroleofTLRstimulationintheinductionofTcellresponses.þ4.2.IndirectcontrolofCD4TcellresponsesþWhileitseemsclearthatPRRscancontrolCD4Tcellresponsedirectlyundersomeconditions,theyarebestknownfortheirabilitytoinstructtheresponseindirectlybyinducingtheupregulationofcostimulatorymoleculesandthesecretionofcytokinesand/ortypeIinterferonsbyAPCs.ItisthisinteractionbetweenAPCsandTcellsthatshapestheensuingTcellresponse.Forthepurposeofthischapter,wewanttofocusmainlyontherolesofIL-1andIL-6inthecontrolofadaptiveimmunityasthesecretionofthesetwocytokinesisaparticularlyprominentfeatureofPRRactivationandbecausethereisconsiderableevidencethatthesetwocytokinesplaycriticalrolesincontrollingTcellsresponses.þ4.2.1.TheeffectsonIL-1onCD4TcellresponsesTworelatedgenesencodeIL-1.IL-1aiswidelyexpressedandcontainsaleadersequenceforthesecretionoftheproteinwithoutfurtherprocessing.Itisusuallyassociatedwiththeplasmamembraneoftheproducingcellandthusactslocally.Incontrast,theleaderlessIL-1b,whoseexpressionismostlyrestrictedtoAPCsandneutrophils,requirescaspase-1foritscleavagefrompro-IL-bandsubsequentsecretionasasystemicallyactingprotein.Despitethefundamental 102DominikSchentenandRuslanMedzhitovdifferencesintheregulationofIL-1aandIL-b,theirbiologicalactivitiesarethoughttobesimilar.AsIL-1isapleiotropiccytokinethatactsonmanycelltypesandtissues,ithasbeendifficulttodistinguishbetweenitsdirectandindirectþeffectsonCD4Tcellresponses.Nonetheless,itisclearthatIL-1controlsseveralaspectsofTcellresponsesdirectly(Dinarello,2009;SimsandSmith,2010).IL-1isinvolvedascostimulatortogetherwithantigeninþthegenerationofbothaprimaryaswellasasecondaryCD4Tcellresponse,inpartbyfacilitatingIL-2signalingthroughtheupregulationoftheIL-2receptora(CD25)andpreventingofapoptosisthroughtheactivationofNF-kBandPI3K(Ben-Sassonetal.,2009;ONeill,2008).Thus,þIL-1servesasageneralactivatorofCD4Tcellresponses,eventhoughthepreciserolesofthiscytokineinthisprocessarenotcompletelyunderstood.Inrecentyears,IL-1receivedconsiderableattentionbecauseofitsþeffectsinTH17differentiation.Naı¨veCD4TcellsexpressverylowlevelsoftheIL-1RbutupregulateitfollowingactivationthoughtheTCRandCD28(Chungetal.,2009).TH17cellsexpresshighlevelsoftheIL-1R,andmultiplestudieshaveshownthatIL-1promotesthedifferentiationofþnaı¨veCD4TcellsintoTH17cellsinvitro(Acosta-Rodriguezetal.,2007a;Chungetal.,2009;Kryczeketal.,2007;Wilsonetal.,2007).IL-1þsignalinginCD4TcellsisalsorequiredfortheinductionofTH17cellsþinvivoand,consequently,CD4TcellsdeficientinIL-1signalingfailtoinduceEAEandcolitis,whicharebothTH17-drivendiseases(Chungetal.,2009;Fukataetal.,2008;Suttonetal.,2006;Tomitaetal.,2008).TheprecisefunctionofIL-1signalinginthedifferentiationofTH17cellsisstillnotwelldefined.However,apicturehasbeguntoemergethatsuggestsafunctionofIL-1intheearlyphaseofthisprocess(Chungetal.,2009).Inparticular,IL-1inducestheexpressionofthetranscriptionfactorsRORgtandIRF4,bothofwhicharerequiredforTH17development,andtriggersthemTORpathwaytoinduceproliferationofTH17(Chungetal.,2009;Gulenetal.,2010).Inaddition,IL-1appearstosynergizewithIL-23toensurethemaintenanceofTH17cells.ItisstilluncleartowhatextentTH1cellsexpresstheIL-1R.Somereportsdonotdetectthereceptor,whileothersfindevidencefortheexpressionofIL-1RonTH1cells,albeitatmuchlowerlevelsthanTH17cells(Chungetal.,2009;Guoetal.,2009;Taylor-RobinsonandPhillips,1994).IrrespectiveofthepreciseregulationofIL-1RfollowingtheþactivationofCD4Tcells,however,IL-1appearstobeinvolvedinthegenerationofTH1responses.TheexogenousadministrationofIL-1enhancesTH1responsesandbonemarrowchimerasharboringIL-1R-deficientTcellsgeneratereducednumbersofTH1cellsduringthecourseofEAE(Ben-Sassonetal.,2009;Chungetal.,2009).Therefore,IL-1playsaroleinthegenerationofbothTH1andTH17responses.Incontrast,theIL-1-relatedcytokineIL-18seemstobemoreexclusivelylinkedtothe TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem103generationofTH1responses.TH1cellsexpresshighamountsofIL-18RinaT-bet-dependentfashionandIL-18synergizeswithIL-12toinduceINFg.Inthisregard,thefunctionofIL-18resemblesthatofIL-1andIL-33,namelythatitreinforcestheTH1lineagedecisionlikeIL-1doesforTH17cellsandIL-33forTH2cells(Guoetal.,2009).Thus,membersofþtheIL-1familyappeartobeinvolvedinboththeactivationofCD4Tcellsaswellasmaintainingthesubsequentlineagecommitmentdecision.þInadditiontoitseffectsonthedevelopmentofspecificCD4Teffectorsubsets,IL-1isalsoinvolvedintheregulationoftheinteractionbetweeneffectorTcellsandTregs.TregsexpresstheIL-1Rthemselves(Chaudhryetal.,2009;Merceretal.,2010).WhiletheeffectsofIL-1onTregfunctionarenotclearlyunderstood,ithasbeensuggestedthatIL-1enablesTcellresponsesbyblockingthesuppressivefunctionofTregs(OSullivanetal.,þ2006).Alternatively,TregsmaydepriveCD4effectorTcellsofIL-1(Chaudhryetal.,2009).Moreover,IL-1hasbeenimplicatedinenablingtheconversionofinducedTregs(iTregs)intoTH17cells(Chungetal.,2009).þ4.2.2.TheeffectsonIL-6onCD4TcellresponsesSimilartoIL-1,IL-6isapleiotropiccytokinethatisintimatelyinvolvedinthecontrolofTcellresponses.TheIL-6signalingcomplexconsistsofthespecificIL-6Rachainandthemorepromiscuoussignalingcomponentgp130thatisalsoacommoncomponentofothercytokinereceptorssuchasthereceptorsforLIF,IL-11,andoncostatin-M.SignalsemanatingfromtheIL-6RaretransducedmainlybyJAK1andthenrelayedbyStat3,althoughStat1playsalsoaroleinthisprocess.Importantly,IL-6RsignalingalsoactivatestheMAPKandPI3KpathwaysandactivationofAktbythePI3KpathwayhasbeenimplicatedintheroleofIL-6asasurvivalfactor.InadditiontothemoreconventionaltransmembraneformofIL-6Ra,somecelltypes(e.g.,macrophagesandneutrophils)alsoproduceasolubleversionofthereceptor(sIL-6Ra),whichcanbindtogetherwithIL-6togp130andthusinduceasignalingp130-expressingcells.Thephysiologicalrelevanceofthisprocess,whichisreferredtoastrans-signaling,inTcellbiologyisnotfullyunderstood.IL-6trans-sig-nalinghasbeenimplicatedintheadvancementofchronicinflammatorydiseases(Rose-Johnetal.,2006).RecentevidencesuggeststhattheþexpressionofIL-6RaisrestrictedtoCD62Lnaı¨veandcentralmemoryþCD4Tcells,whereaseffectorTcellsdownregulateIL-6Ra(Jonesetal.,2010).Consistentwiththisexpressionpattern,TH17effectorTcellsseemtorequireIL-6trans-signalingforthelocallineagemaintenanceintheinflamedtissue,whereneutrophilsareamajorsourceofsIL-6Ra(Hurstetal.,2001;Jonesetal.,2010).þIL-6positivelyinfluencesthesurvivalofCD4Tcells.Forexample,itinducestheexpressionofBcl-2anddownregulatesFasL,thusprotectingthecellsfromactivation-inducedcelldeath(Ayroldietal.,1998;Dienz 104DominikSchentenandRuslanMedzhitovetal.,2009;KishimotoandSprent,1999;Lotzetal.,1988;Teagueetal.,1997).TheantiapoptoticfunctionofIL-6hasalsobeenimplicatedintheþpositiveinfluenceofIL-6ontheexpansionofactivatedCD4Tcellsfollowingimmunization(Rochmanetal.,2005).However,thiseffectmayalsoreflectanotherproposedfunctionofIL-6,namelythatitrendersþnaı¨veCD4TcellsinsensitivetothesuppressiveeffectsofTregs(PasareandMedzhitov,2003).Thus,TH1responsesareseverelycompromisedinIL-6-deficientmiceimmunizedwithproteininthepresenceofLPS,butcanberestoredupontransientdepletionofTregs.InadditiontoitsroleinactivationofTH1cells,IL-6isimportantforthedifferentiationofTH17cells,whichalsoinvolvesTGF-b(Acosta-Rodriguezetal.,2007a;Bettellietal.,2006;Miossecetal.,2009;Veldhoenetal.,2006).ThesetriggersarethoughttoleadtotheautocrineactivationofthecellsbyIL-21,whichexpandsthecells(Kornetal.,2007;Nurievaetal.,2007;Zhouetal.,2007).Interestingly,theexpressionofIL-21isitselfcontrolledbyIL-6(Dienzetal.,2009).IL-23thenstabilizesthedifferentiationprogramandinduceseffectorcytokinessuchasIL-17(Manganetal.,2006;Veldhoenetal.,2006;Zhouetal.,2007).IL-6alsoinfluencesthebalancebetweenTH17cellsandiTregs.TheadditionofIL-6inhibitstheTGFb-drivenexpressionofFoxP3andpromotestheþexpressionofRORgtinvitro(Bettellietal.,2006).Consequently,CD4TcellsarethoughttodifferentiateintoiTregsathigherlevelsinIL-6-deficientmiceuponimmunization(Kornetal.,2007).Interestingly,thenegativeregulationofiTreginductionbyIL-6mightinvolveIL-6trans-signaling,whichhasbeenshowntoinducetheTGFbsignalinginhibitorSMAD7(Dominitzkietal.,2007).However,TregscanexpresstheIL-6Rathemselves,soIL-6mayalsoactonthesecellsdirectly.þInadditiontoitsinvolvementinTH17differentiation,otherCD4TcellsubsetsmayalsorelyonIL-6fortheirgeneration.Recently,IL-6hasbeenimplicatedinthegenerationoffollicularThelpers(TFH)cells(Nurievaetal.,2008,2009).TFHcelldifferentiationisgovernedbythelineagedefiningtranscriptionfactorBcl6(Johnstonetal.,2009;Nurievaetal.,2009).Bcl6isinducedbyIL-6invitro,suggestingthatIL-6drivesthedifferentiationofTFHcells(Nurievaetal.,2008,2009)Consistentwiththisidea,TFHcellsalsodependonIL-21fortheirdevelopment,whichisalsoþinducedbyIL-6(Nurievaetal.,2008).However,CD4TcellscarryingaTCRtransgeneareabletogenerateTFHcellsfollowingtheirtransferintoIL-6-deficientmice,indicatingthatIL-6iseithernotessentialorredun-dantinvivo(Poholeketal.,2010).þTheeffectsofbothIL-1andIL-6onthegenerationofCD4Tcellresponsesareremarkablysimilar.BothhavebeenimplicatedinthereleasefromTreg-mediatedsuppression,thedifferentiationofTH17cells,andintheshiftfromatoleranttoaninflammatorystate,resultingintheconversionofTregsintoTH17cells.Hence,IL-1andIL-6are TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem105þpresumablyactinginacooperativefashiononCD4Tcells,eventhoughtheirintracellularsignalingpathwaysarenonoverlapping.Thisnotionisfurtherillustratedbytheobservationthatundersomeconditions,IL-1inducestheexpressionofIL-6Ra(Chungetal.,2009).DespitethefundamentalinvolvementofbothIL-1familymembersþandIL-6onthegenerationofCD4Tcellresponses,multiplemicrobesþcantriggerCD4Tcellresponsesthatareindependentofthesecytokines.Forexample,theTH1responsetoL.monocytogenes,Salmonellatyphimirium,T.gondii,LCMV,andHSV-1requiresneitherIL-1norIL-18(Kursaretal.,þ2004;LaRosaetal.,2008;Seibertetal.,2010;Zhouetal.,2009).TheCD4TcellresponsetoL.monocytogenesalsodoesnotdependonIL-6(SimoneNish,DominikSchenten,IgorBrodsky,RuslanMedzhitov,unpublished).TheseexamplesaresurprisinggiventheapparentimportanceofIL-6þandmembersoftheIL-1familyofcytokinesinthegenerationofCD4Tcellresponsesundervariousexperimentalconditions.MostoftheþstudiesthatidentifiedsuchrequirementsassessedtheCD4Tcellresponseinvitroorfollowingproteinimmunizationinvivo,althoughsomestudiesusingmicrobialinfectionssuchasInfluenzafurtherconfirmþtheimportanceofthesecytokinesinthegenerationofCD4Tcellresponses(Ichinoheetal.,2009;Longhietal.,2008).Ontheotherhand,theapparentlackofarequirementforIL-1,IL-18,orIL-6forprimaryþCD4TcellresponsesagainstavarietyofinfectionssuggeststhattheþrequirementofthesecytokinesfortheinductionofCD4Tcellresponsesisnotuniversal.Itisthereforepossiblethatduringthecourseofsomeinfections,alternativecytokinesarereleasedthatforsomecellularpro-cessescarrysimilarinformationasIL-1orIL-6do.Forexample,cytosolicinfectionsmaycausethesecretionoftypeIinterferonsorIL-15thatþpreventCD4Tcellsfromundergoingapoptosisorrenderthemrefrac-torytoTreg-mediatedsuppression.ThelatterscenariohasindeedbeenproposedforIL-15(BenAhmedetal.,2009).Inaddition,wealsospeculateþthatseeminglysimilarCD4Tcellresponsesarenotnecessarilyidentical.Thus,bothInfluenzaandLCMVmayinducethegenerationofdifferentsubsetsofTH1cells,withtheformerbeingIL-1dependentandthelatterIL-1independent.TH1responsesareusuallyidentifiedbytheabilityofþtheCD4TcellstosecreteIFNg.However,additionalcytokinesorotherfactorsinvolvedineffectorfunctionmaybedifferentiallysecretedamongthesubsetsandthusmoresuitedtodistinguishbetweendifferentsubsets.SuchaconceptiscurrentlyemerginginthecontextofTH17differentiation,whichappearstobemorecomplexasitmaynotalwaysinvolveIL-1orIL-6.Indeed,TH17cellscanalsobedifferentiatedinvitrobyTGFbandIL-21intheabsenceofIL-6(Kornetal.,2007).Moreover,IL-6-orTGFb-independentTH17responsescanbegeneratedundercertaincircumstancesinvivo(Ghoreschietal.,2010;Kornetal.,2008).Importantly,TH17differentiationcanberestoredinIL-6-deficientmicein 106DominikSchentenandRuslanMedzhitovtheabsenceofTregs,atleastfollowingtheimmunizationwithCompleteFreundsAdjuvant(Kornetal.,2007).Thus,thereseemstobeaconsiderabledegreeofplasticityinthedifferentiationofTH17cells,whichmayreflecttheexistenceofdistinctTH17subsets.TheexistenceofdistinctTH17subpopulationsisalsosupportedbytheobservationthatIL-23appearstodrivethedifferentiationofTH17cellsthatcausediseaseintheEAEmousemodelofmultiplesclerosis,whereasTGFbandIL-6caninduceTH17cellsthatcanalsosecretetheanti-inflammatorycytokineIL-10(Ghoreschietal.,2010;McGeachyetal.,2007).5.BCELL-INTRINSICCONTROLOFHUMORALIMMUNERESPONSESBYPRRSTheroleofTLRligandsinBcellactivationhasbeenappreciatedsincetheearlydaysofBcellimmunology.LPSistheprototypicalT-independenttypeI(TI-1)antigenthatinducesanIgG3-dominatedantibodyresponse.However,thetraditionalunderstandingofT-dependent(TD)antibodyresponsesassumedthatBcellsrelyonBcellreceptorstimulationandTcellhelpfortheiractivationandthatthelattercomesfromTcellsthathavebeenactivatedbyPRR-exposedDCs.Thus,innatemeansofself/nonselfdiscriminationwereconsideredtooccursolelyinDCs.ItwasthereforesurprisingthatTLRstimulationonBcellsisanimportantcontributortothegenerationofefficientT-dependentantibodyresponses.ConsistentwiththeinductionofTH1byTLRs,IgG2cantibodyresponseswereparticularlyaffectedintheabsenceofLPS-inducedTLRsignaling(PasareandMedzhitov,2005).Sincethisinitialobservation,similarfind-ingshavebeenmadeinothersystemsandconfirmedthatBcell-specificTLRactivationbyLPS,RNA,andCpGDNAisimportantfortheIgG2cresponsetoimmunizations,virus-likeparticles,andseveralbacterialandviralinfections(Barretal.,2009;Guayetal.,2007;Heeretal.,2007;Jegerlehneretal.,2007;RuprechtandLanzavecchia,2006).Likewise,Bcell-specificTLRsignalswerealsorequiredfortheinductionofanti-body-drivenautoimmunediseases(Herlandsetal.,2008;Leadbetteretal.,2002;Williametal.,2005).WhilethesefindingssupportedthenotionthatBcell-intrinsicTLR-mediatedsignalsenhanceormodulatetheBcellresponse,twootherexperimentssuggestedthatTLRsarerequiredneitherspecificallyinBcellsnoringeneralforthegenerationofT-dependentantibodyresponses(Gavinetal.,2006;Meyer-Bahlburgetal.,2007).Thesefindingswereinitiallyconfusing,yetitseemsclearnowthatthediscrepanciesareduetotheuseofnativeproteinantigenintheformergroupofstudiesversushaptenatedproteinantigensinthelatterstudies(PalmandMedzhitov,2009). TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem107ThestudyoftheroleofPRRsignalsinthegenerationofantibodyresponsesarecomplicatedbysuchsubtledifferencesamongtheimmunizingantigens.Itislikelythatdifferencesintheaffinity,avidity,orchemicalnatureoftheimmunizingantigenaswellasthechoiceofadjuvantandrouteofimmunizationfundamentallyinfluencetheoutcomeofadaptiveimmuneresponses.Withthisinmind,whatthenmightcausethedifferenceinTLRdependencebetweenhaptenatedandnativeproteins?OnepossibilityisthatthechemicalpropertiesofthehaptenitselfrendertheproteinimmunogenicasthehaptenistriggeringaninnatepathwaythatisredundanttotheTLRpathway.Thepathwaymaythereforebepartofanantibodyresponsethatisdirectedagainstharmfulxenobiotics(PalmandMedzhitov,2009).Alternatively,haptena-tionofproteinscreatesmultivalentepitopes,particularlyinthecontextofcommonlyusedadjuvantslikealumandmineraloil.Thedegreeofrepeti-tionofepitopesonparticlesinfluencesthemagnitudeofaTDantibodyresponse,irrespectiveoftheoverallconcentrationoftheparticles(Jegerlehneretal.,2002).Interestingly,defectsincomplementfixationrequireahigherdegreeofrepetitivenessinordertoinduceanantibodyresponseofsimilarmagnitude.Thus,complementlowerstheactivationthresholdoftheBCRbybindingtoCD21.ItisthereforepossiblethatTLRactivationhastheanalogouseffectinthatitconvertsweakantigenswithalowdegreeofrepetitiveepitopesintohighlyimmunogeniconesbyprovidingastrongeractivationsignaltotheBcells.InadditiontotheirroleinBcellactivation,TLRsalsoshapethenatureoftheensuingBcellresponse.Bcell-intrinsicTLRactivationhasbeenimplicatedingeneratinganIgG2cresponsethatcanoccurattheexpenseofanIgG1response(Jegerlehneretal.,2007;PasareandMedzhitov,2005).However,theunderlyingmechanismsforthiseffectarelessclear.OnepossibilityisadirectinfluenceofTLRonclassswitchrecombination(CSR;Jegerlehneretal.,2007).ConsistentwiththisnotionisthefindingthatBcell-intrinsicTLRsignalingactivatesgerm-linetranscriptionoftheIgconstantregions.Alternatively,Bcell-intrinsicTLRsignalingappearsalsotoinfluenceCSRindirectlybyfacilitatingthedifferentiationintoTH1cells(orTFHcells),whichsecreteIFNgthatinducesCSRtoIgG2c.SuchanexamplewasobservedduringSalmonellaentericainfections,inwhichtheTH1andTH17responserequiredBcell-derivedIL-6orIFNg(Barretal.,2009).Interestingly,theinductionoftheprimaryTcellresponsewasdependentonBcell-intrinsicMyD88butnotBCRsignals,whereasthememoryTcellresponserequiredsolelyBCR-mediatedsignals.AsmanyofthestudiesontheBcell-intrinsicroleofTLRsignalinginvolveMyD88-deficientmice,itisimportanttonotethatMyD88signalinghasalsobeenimplicatedinthesignaltransductionoftwoadditionalpathways.First,MyD88appearstoassociatewiththeIFNgreceptorinordertostabilizethemRNAofIFNg-inducedgenes(SunandDing,2006).Second,MyD88 108DominikSchentenandRuslanMedzhitovseemstoregulateCSRduringTIandperhapsalsoTDantibodyresponsesinaTLR-andIL-1R-independentmannerthatwasdependentontheBAFFandAPRILreceptorTACI(Heetal.,2010).ItthereforepossiblethatsomeoftheBcell-intrinsiceffectsofTLRsignalingareinfactmediatedbyothercytokineslikeIFNg,BAFF,APRIL,orevenmembersoftheIL-1family.6.PATHOLOGICALCONSEQUENCESOFDEFECTIVEPRRSIGNALINGINHUMANSMostofourknowledgeaboutthemechanismsofinnateinstructionofadaptiveimmunityisderivedfromtheanalysisofcelllinesandmice.Geneticmutationshaveprovidedvaluableinsightsintothefunctionofthehumanimmunesystemanditsinteractionwiththeenvironment(Fischer,2007).Mutationsaffectinginnateimmunity,ingeneral,andPRRsignaling,inparticular,areveryrare,thusillustratingthegeneralimportanceoftheinnateimmunesystemanditssignalingpathways.Nonetheless,muta-tionscausingafunctionalimpairmenthavebeenidentifiedingenesofseveralPRRsignalingpathwaysinhumans.Themostprominentexam-plesaremutationsinTLRsandthesignalingadaptorsMyD88andIRAK-4aswellasmutationsinIL-12oritsreceptor(Altareetal.,1998;Casrougeetal.,2006;Fieschietal.,2003;Georgeetal.,2010;Kuetal.,2007;MischandHawn,2008;Picardetal.,2002,2003;vonBernuthetal.,2008;Zhangetal.,2007).Morerecently,humanmutationsaffectingDectinandNLRsignalinghavealsobeenidentified(Glockeretal.,2009;Hugotetal.,2001;Oguraetal.,2001).GeneticpolymorphismsinmosthumanTLRshavebeenassociatedwithanincreasedrateofinfectionsintheafflictedindividuals.PatientsdeficientofMyD88orIRAK-4signalingsufferfrompyogenicbacterialinfections,oftenduetoS.pneumoniaeorS.aureus(Kuetal.,2007;Picardetal.,2003;vonBernuthetal.,2008).Likewise,individualswithdefectiveIL-12signalingarecommonlyinfectedbymycobacteria,presumablybecauseoftheirinabilitytogenerateaTH1response(orinsomepatients,aTH17response;deBeaucoudreyetal.,2008).Theseinfectionsusuallystrikeduringchild-hoodandarelife-threateningwithahighrateofmortality.However,thespectrumoftheinfectionsisquitenarrow,particularlyconsideringthecentralimportanceofMyD88andIRAK-4inbothTLRandIL-1signaling.Thediseasescanusuallybemanagedwithproperantibiotictreatmentanddeclineinseveritywithage,resultinginalargelydisease-freestateinadulthood,evenintheabsenceofprophylactictreatment(Bousfihaetal.,2010).Similarly,patientsdeficientofTLR3signalingduetomutationsinthereceptor-encodinggeneitself,thedownstreamsignalingadaptorTRAF3,orinUNC93B1,whichisrequiredforproperintracellularprocessingofthe TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem109endosomalTLRs,sufferfromHSV-1-drivenencephalitis(HSE)inearlychildhoodthatdisappearsinadulthood(Casrougeetal.,2006;PerezdeDiegoetal.,2010;Zhangetal.,2007).However,decliningsusceptibilitywithageisnotauniversalfeatureofPRRsignalingdefectsinhumans.IndividualscarryingahomozygousmutationinCARD9,asignalingadaptordownstreamofDectin-1,Dectin-2,andMincle,sufferfromrecurrentCandidainfectionsthatareassociatedwithahighrateofmortality,presumablyduetoaninabilitytogenerateantifungalTH17responses(Glockeretal.,2009).Moreover,mutationsinDectin-1havealsobeenassociatedwithanincreasedrateofmildCandidainfections(Ferwerdaetal.,2009;Plantingaetal.,2009).TheremarkablynarrowspectrumofinfectionsanddecreasedrateofrecurrentinfectionswithincreasingageinthedocumentedsurvivingpatientswithdefectiveTLRandIL-1signalingcanbeinterpretedasindicationthathumanTLRandIL-1signalingisnotimportantforthegenerationofprotectiveadaptiveimmuneresponsesingeneralandantibodyresponsesinparticular(Bousfihaetal.,2010).However,oneshouldemphasizethatthepatientswiththesesevereimmunodeficienciespresumablywouldnothavesurvivedthebacterialassaultswithoutantibioticinterventionandthatthedevelopmentofasubsequentlyprotectiveadaptiveresponsewasabletooccurundertheprotectionofsuchtreatment.Moreover,thepatientsarealsoprotectedbytheconditionsofimprovedhygieneofthemodernizedworld.Itisquestionablewhethertheirresistancetoinfectionscouldbemaintainedundertheconditionsthatexistedthroughoutmostofhumanevolutionotherthantheperiodofthepast50100years.Finally,asoutlinedinthischapter,innatecontrolofadaptiveimmunityinvolvesmultiplePRRsystemswithoverlappingfunctions.Itisthereforenotsurprisingthatsomereplicatingmicrobestriggerthesealternativesystemsinordertogenerateprotectiveimmunity,whileothersdonot.Thus,CARD9-deficientpatientsfailtocontainfungalinfections,whileMyD88-deficientindividualsdevelopprotectiveimmunityiftheysurvivetheprimaryinfections.Indeed,thereisprecedenceforthissituationinMyD88-deficientmice,whichgenerateanormaladaptiveimmuneresponseuponinfectionwithL.monocytogenesandS.entericaorimmunizationwithBCG(Kursaretal.,2004;Seibertetal.,2010;Wayetal.,2003).Moreover,MyD88-deficiencyinmicedoesnotcauseatotallossofantibodyresponseseveninimmunizationsthatcontainonlyTLRligandsasadjuvant.Instead,itreducesmainlythemagnitudeofantibodyresponses,whichmayprovideprotectioninsomecaseorbecomesufficientfollowingrepeatedimmunizationsorinfections.Inaddition,lossofTLR/MyD88-dependentbarrierimmunityinthegutcanleadtocommensalovergrowth,whichinturnstimulatescompensatoryantibodyproduction(Slacketal.,2009). 110DominikSchentenandRuslanMedzhitovThemutationsmentionedsofarcauseadirectimpairmentoftheimmuneresponseandhenceanincreasedsusceptibilitytoinfections.However,therelationshipbetweenfunctionandinfectiousconsequencedoesnotalwaysappearthatlinear.MutationsintheNOD2genehavebeenassociatedwithahighlyincreasedriskforthedevelopmentofcolitis(Hugotetal.,2001;Oguraetal.,2001).Itthereforeseemedtobecounterintuitiveforloss-of-functionmutationsofaPRRtoresultinadiseasethatischaracterizedbyincreasedinflammation.However,recentfindingsmightexplainthisapparentparadox.WhileNOD2-deficientcellsareindeedimpairedintheirabilitytomountanantibacterialresponse,NOD2-deficientmicearesurprisinglyefficientinthecontrolofintestinalbacteriaanddonotdisplayanincreasedsusceptibilitytocolitis(Kobayashietal.,2005;PauleauandMurray,2003).However,NOD2appearstorestrictTLR2-inducedactivationofNF-kB(Maedaetal.,2005;Neteaetal.,2005).NOD2-deficiencythereforerendersthecellsmoresensitivetotheinductionofproinflammatorycytokinesbyTLR2thatleadstoanenhancedTH1response(Watanabeetal.,2004).Thus,NOD2mayinducediseasebyalteringthesignalingstrengthsofotherPRRs.7.CONCLUSIONSInthepastfewyears,manyofthebasicprinciplesofinnatecontrolofadaptiveimmunityhavebecomeclearer.ManyofthePRRshavebeenidentified,andtheirbasicsignalingpathwayshavebeendefinedaswell.Inaddition,wearecurrentlyseeingadramaticincreaseofourunderstandingoftheregulationofTandBcellresponsesbytheinnateimmunesystem.Theseadvancesareshiftingthefocustonewquestionsthatwillfeatureprominentlyintheinvestigationofinnatecontrolofadaptiveimmunityinthenextfewyears.AfewintriguingexamplesofthesequestionsaddresstheidentificationofmicrobialantigensbyintracellularPRRs,theinterplaybetweendifferentPRRs,andtheþexistenceandpossibleinnateinstructionofnovelCD4Tcellsubsets.Asoutlinedpreviously,westillhavenotfullygraspedhowtheresponseofaspecificPRRdiffersbetweenvariouscelltypesandwhatthismeansfortheinductionofadaptiveimmunity.ThecooperationbetweendifferentPRRsintheinstructionoftheadaptiveimmuneresponserequiresfurtherinvestigation.Thus,itwillbeinterestingtodeterminetowhatextentPRRsotherthanTLRsaretrulycapabletodrivetheadaptiveimmuneresponsebythemselves.Moreover,itwillbeimportanttoanalyzehowthecoactivationoftwoormoreclassesofPRRsinfluencesthebalancebetweenthevariousTcellsubsets,forexample,betweenTH1andTH17responses.Thiswillcertainlybeimportantinthecontextofcoinfections.Finally,itwillbecriticaltoinvestigatetheeffectsofinflammasome-mediatedinstructionofadaptiveimmunity,in TheControlofAdaptiveImmuneResponsesbytheInnateImmuneSystem111particular,asitappearsthatthesesignalscandominateoverRLR-drivensignalsasshownforRSVinfections(Bhojetal.,2008;Sabbahetal.,2009).TherecognitionofPAMPsbyPRRsmarksthemicrobialoriginofantigens.APCshavebeenshowntorequirethedirectrecognitionofPAMPsinordertoinduceadaptiveimmuneresponses(SporriandReiseSousa,2005),inpartbecausePAMPsinducethepreferentialpresenta-tionofantigenamongtheseaofself-antigens(BlanderandMedzhitov,2004).Forextracellularpathogens,thisusuallyinvolvestherecognitionofPAMPsthatarephysicallyassociatedwiththeantigen(eitherintheformofamicrobeorartificiallybyadjuvants)bymembrane-boundPRRs.Inintracellularinfections,theAPCsareoftennottheinfectedcells.Thus,thePAMPsandantigensarenotphysicallyassociated.InnatecontrolofadaptiveimmunitybycytosolicPRRsthereforefacestheconceptualproblemoflinkingtheinformationprovidedbythePRRtothepresentedantigen.Thispuzzlehasnotbeensolvedyet,althoughonepossibilitymightinvolvetwosimultaneoussignalsfortheactivationoftheAPCs.OnecouldbethereleaseoftypeIinterferonsorothercytokinesbyinfectedcells,whiletheothercouldbederivedfromthephagocytosisofinfectedcellsbytheAPCsandthesubsequentrecognitionoftheviralnucleicacidbyTLRs(Schulzetal.,2005).þAsmentionedearlier,thepossibilitythatthevariousCD4Tcellsubsetsthemselvesmightcompriseseveraldistinctsubsetsisaprovocativeidea.Inþparticular,thedistinctionofpathogenicversusprotectiveCD4Tcells,whichhasbeensuggestedforTH17cellsinthecontextofEAE,isveryintriguing.Itwillbeimportanttodeterminetowhatextentthesesubsetsdoindeedexistandifso,whethertheytrulyreflectdistinctdifferentiationþstatesormerelydistinctactivationstatesofthesameCD4Tcellsubset.Regardlessofthelatterquestions,though,itislikelythattheinnateimmunesystemisinstrumentalinshapingthesestates.Despitethetremendousprogressmadeoverthepastdecade,manyfundamentalquestionsregardingcontrolofimmuneresponsesremainunanswered.ThecharacterizationofPRRshaselucidatedthemechanismsofimmunogenicity.However,itisbecomingincreasinglyclearthatadditionallayersofcontrolmayexistthatdeterminethechoiceofeffectorclass,themagnitudeandthedurationoftheimmuneresponse.Howtheseregulatorymechanismsoperateinthecontextofinfectionsisanexcitingareaforfutureinvestigation.ACKNOWLEDGMENTSWeapologizetoallthoseinvestigatorswhoseworkwewereunabletocitebecauseofspaceconstraints.WethankNoahPalm,IgorBrodsky,andMarcSchmidt-SupprianforhelpfuldiscussionsandcriticalreadingofthechapterandappreciatethesupportoftheHowardHughesMedicalInstitute(R.M.)andtheCancerResearchInstitute(D.S.). 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