調(diào)節(jié)性T細胞的課件資料

調(diào)節(jié)性T細胞的課件資料第1頁/共40頁MilestoneforTregcelldiscovery第2頁/共40頁AspecialCD4+TcellTregisaspecialCD4+TcellMostCD4+TcellsbelongtoTh1orTh2But5%--10%ofCD4+TcellsbelongtoneitheronewhichiscalledCD4+CD25+regulatorTcells第3頁/共40頁HeterogeneousgroupsofTregcellsNaturalTregcells(nTreg)InducedTregcellsiTregTh3cells(TGF-)Tr1(IL-10)RegulatoryCD8+TcellRegulatoryNKTcellCD4-CD8-(DN)Tcells

Tcells第4頁/共40頁HowTregsarise??THYMUS

(nTreg,CD25+;SUPPRESSAUTOIMUNITY)PERIPHERAL

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

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

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

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

第18頁/共40頁Tregcellmediatedphenomenon

BystandersuppressionSuppressiveactivityofTregcellsrequirestheir

prioractivationthroughtheirTcellreceptor;Onceactivated,Tregcellssuppressinan

antigen-nonspecificway;

Tregcellswithoneantigenspecificitycan

suppresseffectorTcells(Teffcells)with

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

第23頁/共40頁MultipleArenaofTreg第24頁/共40頁TregcellinfluenceotherTcellsSuppresstheproliferation/cytokinereleaseofbothCD4andCD8TeffcellsinvitroPreventCD8+TcellsfromdifferentiationintoeffectorTcellsbutnotproliferationinvivoAlterthedifferentiationofna?veCD4+TcellintoIL-10/TGF-bsecretingTcells第25頁/共40頁PreventCD8+TcellsfromdifferentiationintoeffectorTcellsbutnotproliferationinvivo第26頁/共40頁Alterthedifferentiationofna?veCD4+TcellintoIL-10/TGF-bsecretingTcellsNaiveCD4+TcellcoulddifferentiateintoIL-10orTGF-secretinginducedTregcellsinthepresenceofTregcellsininvivoandinvitroConsistentwiththephenomenonofinfectioustolerance/linkedsuppression第27頁/共40頁PRACTICALCONSEQUENCESANDAPPLICATIONS第28頁/共40頁EffectsofTregdeficiencyinmice第29頁/共40頁EffectsofTregdeficiencyinhumans第30頁/共40頁第31頁/共40頁第32頁/共40頁第33頁/共40頁LimitationtotargetingCD25forTregdepletionCD25,acomponentoftheIL-2receptorcomplex,isalsoupregulatedonconventionalactivated(vaccine-induced)Tcells.InterferewithanongoingprotectiveimmuneresponseagainstsubclinicallevelsofpathogenicinfectionTregreboundwithtimeAsignificantfractionofTreg(10-30%),especiallyrecentlyactivatedTreg,havedownregulatedCD25.Depletionisglobal-riskofautoimmunepathology第34頁/共40頁OtherTreg-specificmarkersGITR,Lag-3,CTLA-4,CD103-expressedonthecellsurfacebut,likeCD25,notspecific.Foxp3ExpressionexclusivelyrestrictedtoTregMasterregulatorofsuppressivephenotypeCD4+CD25+foxp3aswellasCD4+CD25-foxp3Treg.第35頁/共40頁StimulateaCD8+CTLresponseagainstfoxp3Foxp3isanuclearprotein-cannotuseantibodiesorONTAK?-likereagentsfordepletionoffoxp3expressingcell