Ncf1 (p47phox) Is Essential for Direct Regulatory T Cell Mediated Suppression of CD4+ Effector T Cells 英文参考文献.docVIP

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Ncf1 (p47phox) Is Essential for Direct Regulatory T Cell Mediated Suppression of CD4+ Effector T Cells 英文参考文献.doc

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Ncf1(p47phox)IsEssentialforDirectRegulatoryTCellMediatedSuppressionofCD4EffectorTCells英文参考文献

Ncf1(p47phox)IsEssentialforDirectRegulatoryTCell MediatedSuppressionofCD4+EffectorTCells OlgaEfimova1,PhilippeSzankasi2,ToddW.Kelley1,2* 1DepartmentofPathology,UniversityofUtah,SaltLakeCity,Utah,UnitedStatesofAmerica,2ARUPLaboratories,SaltLakeCity,Utah,UnitedStatesofAmerica Abstract Background: Multiple mechanisms have been advanced to account for CD4+FOXP3+ regulatory T cell (Treg)-mediated suppressionofCD4+effectorTcells(Teffs)butnoneappeartocompletelyexplainsuppression.Previousdataindicatesthat Tregsmayaffectthemicroenvironmentredoxstate.GiventheinherentredoxsensitivityofTcells,wetestedthehypothesis thatoxidantsmaymediatethedirectsuppressionofTeffsbyTregs. Methodology/Principal Findings: Tregs and Teffs were isolated from the spleens of wild type (WT) C57BL/6 mice or Ncf1(p47phox)-deficientC57BL/6micewhichlackNADPHoxidasefunction.TeffswerelabeledwithCFSEandco-cultured withunlabeledTregsatvaryingTreg:Teffratiosinthepresenceofanti-CD3/CD28coatedbeadsfor3daysinsuppression assays.Treg-mediatedsuppressionwasquantifiedbyflowcytometricanalysisofCFSEdilutioninTeffs.Thepresenceofthe antioxidantsn-acetylcysteine(NAC)or2-mercaptoethanolorinhibitorsofNADPHoxidase(diphenyleneiodoniumandVAS- 2870)resultedinreducedWTTreg-mediatedsuppression.TheobservedsuppressionwasinpartdependentuponTGFbasit was partially blocked with neutralizing antibodies. The suppression of Teff proliferation induced by exogenous TGFb treatment could be overcome with NAC. Ncf1-deficient Teff were slightly but significantly less sensitive than WT Teff to suppression by exogenous TGFb. Ncf1-deficient Tregs suppressed Ncf1-deficient Teff very poorly compared to wild type controls.TherewaspartialbutincompletereconstitutionofsuppressioninassayswithWTTregsandNcf1-deficientTeff. Conclusions/Significance:WepresentevidencethatNADPHoxidasederivedROSplaysaroleinthedirectTregmediated suppressionofCD4+effectorTcellsinaprocessthatisblockedbythiol-containingantioxidants,NADPHoxidaseinhibitors oralackofNcf1expressioninT