GenerationandEffectorFunctionsofRegulatoryLymphocytes:NovartisFoundationSymposium 252.Volume252 EditedbyGregoryBockandJamieGoode CopyrightNovartisFoundation2003.ISBN:0-470-85074-4 GENERATION AND EFFECTOR FUNCTIONS OF REGULATORY LYMPHOCYTES TheNovartisFoundationisaninternationalscienti¢candeducational charity(UKRegisteredCharityNo.313574).KnownuntilSeptember1997 astheCibaFoundation,itwasestablishedin1947bytheCIBAcompany ofBasle,whichmergedwithSandozin1996,toformNovartis.The FoundationoperatesindependentlyinLondonunderEnglishtrust law.Itwasformallyopenedon22June1949. 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NovartisFoundationSymposium252 x+315pages,42¢gures,19tables LibraryofCongressCataloging-in-PublicationData Generationande¡ectorfunctionsofregulatorylymphocytes/[editors,GregoryBockand JamieGoode]. p.cm.^(NovartisFoundationsymposium;252) Includesbibliographicalreferencesandindex. ISBN0-470-85074-4(alk.paper) 1.Lymphocytes.2.Tcells.3.Immuneresponse^Regulation. I.Bock,Gregory. II. Goode,Jamie. III.Series. QR185.8.L9G462003 571.9’6^dc22 2003057598 BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN0470850744 Typesetin101(cid:1) on121(cid:1) ptGaramondbyDobbieTypesettingLimited,Tavistock,Devon. 2 2 PrintedandboundinGreatBritainbyT.J.InternationalLtd,Padstow,Cornwall. Thisbookisprintedonacid-freepaperresponsiblymanufacturedfromsustainableforestry, inwhichatleasttwotreesareplantedforeachoneusedforpaperproduction. Contents SymposiumonGenerationande¡ectorfunctionsofregulatorylymphocytes,heldattheNovartis Foundation,London,9^11July2002 Editors:GregoryBock(Organizer)andJamieGoode ThissymposiumwasbasedonaproposalmadebyMatthiasvonHerrathandJe¡reyBluestone Jean-Francc(cid:1)oisBach Chair’sintroduction 1 ShimonSakaguchi,ShoheiHori,YoshinoriFukui,TakehikoSasazuki, NorikoSakaguchiandTakeshiTakahashi Thymicgenerationandselectionof CD25+CD4+regulatoryTcells:implicationsoftheirbroadrepertoireandhigh self-reactivityforthemaintenanceofimmunologicalself-tolerance 6 Discussion 16 EthanM.Shevach,CiriacoA.Piccirillo,AngelaM.Thorntonand RebeccaS.McHugh ControlofTcellactivationbyCD4+CD25+suppressor Tcells 24 Discussion 36 AdamP.Kohm,PamelaA.CarpentierandStephenD.Miller Regulationof experimentalautoimmuneencephalomyelitis(EAE)byCD4+CD25+regulatory Tcells 45 Discussion 52 ElisaBoden,QizhiTang,HeleneBour-JordanandJe¡reyA.Bluestone The roleofCD28andCTLA4inthefunctionandhomeostasisofCD4+CD25+ regulatoryTcells 55 Discussion 63 ClareBaecher-Allan,JuliaA.Brown,GordonJ.FreemanandDavidA.Ha£er CD4+CD25+regulatorycellsfromhumanperipheralbloodexpressveryhighlevels ofCD25exvivo 67 Discussion 88 v vi CONTENTS FionaPowrie,SimonRead,ChristianMottet,HolmUhligandKevinMaloy ControlofimmunepathologybyregulatoryTcells 92 Discussion 98 GeneraldiscussionI TGFb 106 MariaGraziaRoncarolo,SilviaGregoriandMeganLevings Type1T regulatorycellsandtheirrelationshipwithCD4+CD25+Tregulatorycells 115 Discussion 127 LeonardC.Harrison,NatashaR.SollyandNathanR.Martinez (PRO)insulin- speci¢cregulatoryTcells 132 Discussion 141 Qing-ShengMi,CraigMeagherandTerryL.Delovitch CD1d-restrictedNKT regulatorycells:functionalgenomicanalysesprovidenewinsightsintothe mechanismsofprotectionagainstType1diabetes 146 Discussion 160 EliSercarz,EmanualMaverakis,PetervandenElzen,LouiMadakamutiland VipinKumar SevensurprisesintheTCR-centredregulationofimmune responsivenessinanautoimmunesystem 165 Discussion 171 KathrynJ.Wood,HidetakeUshigome,MahzuzKarim,AndrewBushell, ShoheiHoriandShimonSakaguchi Regulatorycellsintransplantation 177 Discussion 188 KimJ.Hasenkrug CD4+regulatoryTcellsinchronicviralinfection 194 Discussion 199 GeneraldiscussionII 203 MarcaH.M.Wauben,EstherN.M.’tHoenandLeonieS.Taams Modulationof Tcellresponsesaftercross-talkbetweenantigenpresentingcellsandTcells:agive- and-takerelationship 211 Discussion 220 JacquesBanchereau,JosephFay,VirginiaPascualandA.KarolinaPalucka Dendriticcells:controllersoftheimmunesystemandanewpromisefor immunotherapy 226 Discussion 235 vii CONTENTS ChrystelleAssemanandMatthiasvonHerrath Regulationofviraland autoimmuneresponses 239 Discussion 253 GeneraldiscussionIII Activeimmuneregulation 257 MargaretJ.Dallman,BrianChampionandJonathanR.Lamb Notchsignalling intheperipheralimmunesystem 268 Discussion 276 LucienneChatenoud CD3antibodytreatmentstimulatesthefunctionalcapability ofregulatoryTcells 279 Discussion 286 AllanMcIMowat,AnneM.Donachie,LucyA.Parker,NeilC.Robson, HelenBeacock-Sharp,LindsayJ.McIntyre,OwainMillingtonand FernandoChirdo Theroleofdendriticcellsinregulatingmucosalimmunity andtolerance 291 Discussion 302 Indexofcontributors 306 Subjectindex 308 Participants AbulK.Abbas DepartmentofPathology,UniversityofCaliforniaSan Francisco,RoomM590,513ParnassusAvenue,SanFrancisco,CA94143,USA ChrystelleAsseman(NovartisFoundationBursar) LaJollaInstituteforAllergy andImmunology,10355ScienceCenterDrive,SanDiego,CA92121,USA Jean-Francc(cid:1)oisBach(Chair) Laboratoired’Immunologie,Ho“pitalNecker, 161ruedeSe'vres,75743ParisCedex15,France JacquesBanchereau BaylorInstituteforImmunologyResearch,3434Live Oak,Suite205,Dallas,TX75204,USA Je¡reyBluestone UCSFDiabetesCenter,513ParnassusAveBox0540, SanFrancisco,CA94143-0540,USA LucienneChatenoud Laboratoired’Immunologie,Ho“pitalNecker,161ruede Se'vres,F-75743ParisCedex15,France CristinaCuturi INSERMU437,CHUdeNantes,30solJ.Monnet,44093, Nantes,France MargaretDallman DepartmentofBiology,SirAlexanderFlemingBuilding, ImperialCollegeofScience,TechnologyandMedicine,SouthKensington, LondonSW72AZ,UK TerryDelovitch TheJohnP.RobartsResearchInstitute,1400WesternRoad, London,Ontario,CanadaN6G2V4 RichardFlavell DepartmentofImmunobiology,YaleUniversitySchoolof Medicine,HHMI,310CedarStreet,FMB412,Box208011,NewHaven, CT06520-8011,USA DavidHa£er CenterforNeurologicDiseases,HarvardMedicalSchool,77 AvenueLouisPasteur,Boston,MA02115,USA viii ix PARTICIPANTS LeonardHarrison AutoimmunityandTransplantationDivision,TheWalter andElizaHallInstituteofMedicalResearch,TheRoyalMelbourneHospital PO,Parkville,3050Victoria,Australia KimHasenkrug LaboratoryofPersistentViralDiseases,RockyMountain Laboratories,NationalInstituteofAllergyandInfectiousDiseases,Hamilton, MT59840,USA StephenMiller ImmunobiologyCenter,NorthwesternUniversitySchoolof Medicine,303E.ChicagoAvenue,Chicago,IL60611-3072,USA AvMitchison DepartmentofImmunology,WindeyerInstituteofMedical Science,UniversityCollegeLondonMedicalSchool,46ClevelandStreet, LondonW1P6DB,UK AllanMowat DepartmentofImmunologyandBacteriology,WesternIn¢rmary, GlasgowG116NT,UK VirginiaPascual BaylorInstituteforImmunologyResearch,3434LiveOak, Suite205,Dallas,TX75204,USA FionaPowrie UniversityofOxford,SirWilliamDunnSchoolofPathology, SouthParksRoad,OxfordOX13RE,UK MariaGraziaRoncarolo SanRa¡aeleTelethonInstituteforGeneTherapy (HSR-TIGET),ViaOlgettina58,I-20132Milano,Italy ShimonSakaguchi DepartmentofExperimentalPathology,Institutefor FrontierMedicalSciences,KyotoUniversity,53ShogoinKawahara-cho, Sakyo-ku,Kyoto606-8507,Japan EliSercarz TheLaJollaInstituteforAllergyandImmunology,10355Science CenterDrive,SanDiego,CA92121,USA EthanShevach CellularImmunologySection,NIAIDLaboratoryof Immunology,Building10,Room11N315,10CenterDrive,MSC1892,Bethesda, MD20892-1892,USA MatthiasvonHerrath DepartmentofImmuneRegulation,LaJollaInstitute forAllergyandImmunology,10355ScienceCenterDrive,SanDiego,CA92121, USA x PARTICIPANTS MarcaWauben DepartmentofInfectiousDiseasesandImmunology,Facultyof VeterinaryMedicine,UtrechtUniversity,POBox80.165,NL-3508TDUtrecht, TheNetherlands ChristophWalker NovartisPharmaUK,NovartisHorshamResearchCentre, WimblehurstRoad,HorshamRH125AB,UK KathrynWood TheNu⁄eldDepartmentofSurgery,UniversityofOxford, JohnRadcli¡eHospital,HeadleyWay,Headington,OxfordOX39DU,UK