Differential Responses of Human Regulatory T Cells (Treg) and Effector T Cells to Rapamycin 英文参考文献.docVIP

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Differential Responses of Human Regulatory T Cells (Treg) and Effector T Cells to Rapamycin 英文参考文献.doc

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Differential Responses of Human Regulatory T Cells (Treg) and Effector T Cells to Rapamycin 英文参考文献

DifferentialResponsesofHumanRegulatoryTCells (Treg)andEffectorTCellstoRapamycin LauraStrauss,MalgorzataCzystowska,MartaSzajnik,MagisMandapathil,TheresaL.Whiteside* DepartmentofPathology,UniversityofPittsburghSchoolofMedicineandUniversityofPittsburghCancerInstitute,Pittsburgh,Pennsylvania,UnitedStatesofAmerica Abstract Background:Theimmunosuppressivedrugrapamycin(RAPA)promotestheexpansionofCD4+CD25highFoxp3+regulatory Tcellsviamechanismsthatremainunknown.Here,westudiedexpansion,IL-2R-cchainsignaling,survivalpathwaysand resistancetoapoptosisinhumanTregrespondingtoRAPA. Methodology/PrincipalFindings:CD4+CD25+andCD4+CD25negTcellswereisolatedfromPBMCofnormalcontrols(n=21) usingAutoMACS.TheseTcellsubsetswereculturedinthepresenceofanti-CD3/CD28antibodiesand1000IU/mLIL-2for3 to6weeks.RAPA(1–100nM)wasaddedtohalfofthecultures.Afterharvest,thecellphenotype,signalingviathePI3K/ mTORandSTATpathways,expressionofsurvivalproteinsandAnnexinVbindingweredeterminedandcomparedtovalues + + obtainedwithfreshly-separatedCD4 CD25highandCD4 CD25negTcells.Suppressorfunctionwastestedinco-cultureswith + + autologous CFSE-labeled CD4 CD25neg or CD8 CD25neg T-cellresponders. The frequency andsuppressor activityof Treg + + wereincreasedaftercultureofCD4 CD25 Tcellsinthepresenceof1–100nMRAPA(p,0.001).RAPA-expandedTregwere largely CD4 CD25highFoxp3+ cells and were resistant to apoptosis, while CD4 CD25neg T cells were sensitive. Only Treg + + upregulatedanti-apoptoticanddown-regulatedpro-apoptoticproteins.TregexpressedhigherlevelsofthePTENprotein + thanCD4 CD25negcells.ActivatedTreg6RAPApreferentiallyphosphorylatedSTAT5andSTAT3anddidnotutilizethePI3K/ mTORpathway. Conclusions/Significance:RAPAfavorsTregexpansionandsurvivalbydifferentiallyregulatingsignaling,proliferationand sensitivitytoapoptosisofhumaneffectorTcellsandTregafterTCR/IL-2activation. Citation:StraussL,CzystowskaM,SzajnikM,MandapathilM,WhitesideTL(2009)DifferentialResponsesofHumanRegulatoryTCells(Treg)andEffectorTCells toRapamycin.P