调节性T细胞的课件资料

调节性T细胞的课件资料第1页/共40页MilestoneforTregcelldiscovery第2页/共40页AspecialCD4+TcellTregisaspecialCD4+TcellMostCD4+TcellsbelongtoTh1orTh2But5%--10%ofCD4+TcellsbelongtoneitheronewhichiscalledCD4+CD25+regulatorTcells第3页/共40页HeterogeneousgroupsofTregcellsNaturalTregcells(nTreg)InducedTregcellsiTregTh3cells(TGF-)Tr1(IL-10)RegulatoryCD8+TcellRegulatoryNKTcellCD4-CD8-(DN)Tcells

Tcells第4页/共40页HowTregsarise??THYMUS

(nTreg,CD25+;SUPPRESSAUTOIMUNITY)PERIPHERAL

(iTreg,Tr1,Th3;DAMPENIMMUNEREACTIONSTOPATHOGENS)第5页/共40页DevelopmentofTreginthymus第6页/共40页DiversificationofCD4TCellLineages第7页/共40页SearchingforthemarkersofTregcells第8页/共40页MolecularMarkerFunctionCD4+-BindsMHCclassII-ExpressedonThcellsCD25+-ExpressedonmostTregcellsCD3+-EnsuresexpressionofTCRGITR-Negativesignaling-RequiredforsurvivalCTLA-4-BindsCD80/CD86-AntagonizeseffectsofCD28toCD80/86CCR7-MediatesmigrationofTregcellsbacktolymphnodesFoxp3-RequiredfordifferentiationandfunctionofTregcells第9页/共40页NOTE!TherearenoknowncellsurfacemoleculesthatuniquelydistinguishtheCD4+TregcellsfromconventionalactivatedCD4+Tcells!CD25CTLA-4GITRCD4+CD25+RegulatoryTcell第10页/共40页.

FOXP3isthespecificmarker-mediatorofthegeneticprogramgoverningCD25+CD4+Tregcelldevelopmentandfunction第11页/共40页.

FOXP3ControlsRegulatoryTCellFunctionthroughCooperationwithNFATByswitchingtranscriptionalpartners[Fos-Jun(AP-1)vs.FOXP3],NFATconvertstheTcellactivationprogramintothesuppressorprogramofTregs

第12页/共40页.ControlofTregfunctionbyFoxP3第13页/共40页TregactivationandproliferationActivatedbycontactwithDC(evenimmature!).第14页/共40页第15页/共40页第16页/共40页第17页/共40页TraffickingandlocalizationofTregsBlood,lymphoidorgans;varietyofhomingreceptorsnecessaryformigrationtolymphnodes,sitesofinflammation.

第18页/共40页Tregcellmediatedphenomenon

BystandersuppressionSuppressiveactivityofTregcellsrequirestheir

prioractivationthroughtheirTcellreceptor;Onceactivated,Tregcellssuppressinan

antigen-nonspecificway;

Tregcellswithoneantigenspecificitycan

suppresseffectorTcells(Teffcells)with

manyotherdistinctantigenspecificities.第19页/共40页TregcellmediatedphenomenonInfectioustolerance/linkedsuppressionPopulationofsuppressorTcellscreatesaregulatorymilieuandpromotestheoutgrowthofanewpopulationofTregcellswithantigenspecificitiesdistinctfromthoseoftheoriginalTregpopulation.第20页/共40页PossiblemechanismsofactionofTregs第21页/共40页第22页/共40页IDO-indoleamine2,3-dioxygenase

第23页/共40页MultipleArenaofTreg第24页/共40页TregcellinfluenceotherTcellsSuppresstheproliferation/cytokinereleaseofbothCD4andCD8TeffcellsinvitroPreventCD8+TcellsfromdifferentiationintoeffectorTcellsbutnotproliferationinvivoAlterthedifferentiationofnaïveCD4+TcellintoIL-10/TGF-bsecretingTcells第25页/共40页PreventCD8+TcellsfromdifferentiationintoeffectorTcellsbutnotproliferationinvivo第26页/共40页AlterthedifferentiationofnaïveCD4+TcellintoIL-10/TGF-bsecretingTcellsNaiveCD4+TcellcoulddifferentiateintoIL-10orTGF-secretinginducedTregcellsinthepresenceofTregcellsininvivoandinvitroConsistentwiththephenomenonofinfectioustolerance/linkedsuppression第27页/共40页PRACTICALCONSEQUENCESANDAPPLICATIONS第28页/共40页EffectsofTregdeficiencyinmice第29页/共40页EffectsofTregdeficiencyinhumans第30页/共40页第31页/共40页第32页/共40页第33页/共40页LimitationtotargetingCD25forTregdepletionCD25,acomponentoftheIL-2receptorcomplex,isalsoupregulatedonconventionalactivated(vaccine-induced)Tcells.InterferewithanongoingprotectiveimmuneresponseagainstsubclinicallevelsofpathogenicinfectionTregreboundwithtimeAsignificantfractionofTreg(10-30%),especiallyrecentlyactivatedTreg,havedownregulatedCD25.Depletionisglobal-riskofautoimmunepathology第34页/共40页OtherTreg-specificmarkersGITR,Lag-3,CTLA-4,CD103-expressedonthecellsurfacebut,likeCD25,notspecific.Foxp3ExpressionexclusivelyrestrictedtoTregMasterregulatorofsuppressivephenotypeCD4+CD25+foxp3aswellasCD4+CD25-foxp3Treg.第35页/共40页StimulateaCD8+CTLresponseagainstfoxp3Foxp3isanuclearprotein-cannotuseantibodiesorONTAK®-likereagentsfordepletionoffoxp3expressingcell