调节性T细胞课件

MilestoneforTregcelldiscoveryMilestoneforTregcelldiscov1AspecialCD4+TcellTregisaspecialCD4+TcellMostCD4+TcellsbelongtoTh1orTh2But5%--10%ofCD4+TcellsbelongtoneitheronewhichiscalledCD4+CD25+regulatorTcellsAspecialCD4+TcellTregisa2HeterogeneousgroupsofTregcellsNaturalTregcells(nTreg)InducedTregcellsiTregTh3cells(TGF-

)Tr1(IL-10)RegulatoryCD8+TcellRegulatoryNKTcellCD4-CD8-(DN)Tcells

TcellsHeterogeneousgroupsofTregc3HowTregsarise??THYMUS

(nTreg,CD25+;SUPPRESSAUTOIMUNITY)PERIPHERAL

(iTreg,Tr1,Th3;DAMPENIMMUNEREACTIONSTOPATHOGENS)HowTregsarise??THYMUS(nTreg4DevelopmentofTreginthymusDevelopmentofTreginthymus5DiversificationofCD4TCellLineagesDiversificationofCD4TCell6SearchingforthemarkersofTregcellsSearchingforthemarkersofT7调节性T细胞课件8NOTE!TherearenoknowncellsurfacemoleculesthatuniquelydistinguishtheCD4+TregcellsfromconventionalactivatedCD4+Tcells!CD25CTLA-4GITRCD4+CD25+RegulatoryTcellNOTE!CD25CTLA-4GITRCD4+CD25+9.

FOXP3isthespecificmarker-mediatorofthegeneticprogramgoverningCD25+CD4+Tregcelldevelopmentandfunction.10.

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

.11.ControlofTregfunctionbyFoxP3.ControlofTregfunctionbyF12TregactivationandproliferationActivatedbycontactwithDC(evenimmature!).Tregactivationandproliferat13调节性T细胞课件14调节性T细胞课件15调节性T细胞课件16TraffickingandlocalizationofTregsBlood,lymphoidorgans;varietyofhomingreceptorsnecessaryformigrationtolymphnodes,sitesofinflammation.

Traffickingand17TregcellmediatedphenomenonBystandersuppressionSuppressiveactivityofTregcellsrequirestheirprioractivationthroughtheirTcellreceptor;Onceactivated,Tregcellssuppressinanantigen-nonspecificway;TregcellswithoneantigenspecificitycansuppresseffectorTcells(Teffcells)withmanyotherdistinctantigenspecificities.Tregcellmediatedphenomenon18TregcellmediatedphenomenonInfectioustolerance/linkedsuppressionPopulationofsuppressorTcellscreatesaregulatorymilieuandpromotestheoutgrowthofanewpopulationofTregcellswithantigenspecificitiesdistinctfromthoseoftheoriginalTregpopulation.Tregcellmediatedphenomenon19PossiblemechanismsofactionofTregsPossiblemechanismsofaction20调节性T细胞课件21IDO-indoleamine2,3-dioxygenase

IDO-indoleamine2,3-dioxygen22MultipleArenaofTregMultipleArenaofTreg23TregcellinfluenceotherTcellsSuppresstheproliferation/cytokinereleaseofbothCD4andCD8TeffcellsinvitroPreventCD8+TcellsfromdifferentiationintoeffectorTcellsbutnotproliferationinvivoAlterthedifferentiationofnaïveCD4+TcellintoIL-10/TGF-bsecretingTcellsTregcellinfluenceotherTce24PreventCD8+TcellsfromdifferentiationintoeffectorTcellsbutnotproliferationinvivoPreventCD8+Tcellsfromdiffe25AlterthedifferentiationofnaïveCD4+TcellintoIL-10/TGF-bsecretingTcellsNaiveCD4+TcellcoulddifferentiateintoIL-10orTGF-

secretinginducedTregcellsinthepresenceofTregcellsininvivoandinvitroConsistentwiththephenomenonofinfectioustolerance/linkedsuppressionAlterthedifferentiationofn26PRACTICALCONSEQUENCESANDAPPLICATIONSPRACTICALCONSEQUENCESANDAPP27EffectsofTregdeficiencyinmiceEffectsofTregdeficiencyin28EffectsofTregdeficiencyinhumansEffectsofTregdeficiencyin29调节性T细胞课件30调节性T细胞课件31调节性T细胞课件32LimitationtotargetingCD25forTregdepletionCD25,acomponentoftheIL-2receptorcomplex,isalsoupregulatedonconventionalactivated(vaccine-induced)Tcells.InterferewithanongoingprotectiveimmuneresponseagainstsubclinicallevelsofpathogenicinfectionTregreboundwithtimeAsignificantfractionofTreg(10-30%),especiallyrecentlyactivatedTreg,havedownregulatedCD25.Depletionisglobal-riskofautoimmunepathologyLimitationtotargetingCD25f33OtherTreg-specificmarkersGITR,Lag-3,CTLA-4,CD103-expressedonthecellsurfacebut,likeCD25,notspecific.Foxp3ExpressionexclusivelyrestrictedtoTregMasterregulatorofsuppressivephenotypeCD4+CD25+foxp3aswellasCD4+CD25-foxp3Treg.OtherTreg-specificmarkersGIT34StimulateaCD8+CTLresponseagainstfoxp3Foxp3isanuclearprotein-cannotuseantibodiesorONTAK®-likereagentsfordepletionoffoxp3expressingcellsi