Basal LAT-diacylglycerol-RasGRP1 Signals in T Cells Maintain TCRα Gene Expression 英文参考文献.docVIP

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Basal LAT-diacylglycerol-RasGRP1 Signals in T Cells Maintain TCRα Gene Expression 英文参考文献.doc

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Basal LAT-diacylglycerol-RasGRP1 Signals in T Cells Maintain TCRα Gene Expression 英文参考文献

BasalLAT-diacylglycerol-RasGRP1SignalsinTCells MaintainTCRaGeneExpression EvanMarkegard1.,EvanTrager1.,Chih-wenOuYang2,WeiguoZhang2,ArthurWeiss3,4,5,JeroenP. Roose1* 1Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America, 2Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America, 3Department of Medicine, University of California San Francisco, San Francisco, California, United StatesofAmerica,4DepartmentofMicrobiologyandImmunologyandHowardHughesMedicalInstitute,UniversityofCaliforniaSanFrancisco,SanFrancisco,California, UnitedStatesofAmerica,5RosalindRussellMedicalResearchCenterforArthritis,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica Abstract In contrast to the well-characterized T cell receptor (TCR) signaling pathways that induce genes that drive T cell developmentorpolarizationofna?¨veCD4TcellsintothediverseTH1,TH2,TH17andTreglineages,itisunclearwhatsignals maintainspecificgeneexpressioninmaturerestingTcells.RestingTcellsresidinginperipherallymphoidorgansexhibit low-levelconstitutivesignaling.WhereastonicsignalsinBcellsareknowntobecriticalforsurvival,therolesoftonicsignals inperipheralTcellsareunknown.HerewedemonstratethatconstitutivesignalsinJurkatTcelllinesaretransducedviathe adaptermoleculeLATandtheRasexchangefactorRasGRP1tomaintainexpressionofTCRamRNAandsurfaceexpression of the TCR/CD3 complex. Independent approaches of reducing basal activity through the LAT-diacylglycerol-RasGRP pathwayledtoreducedconstitutiveRas-MEK-ERKsignalsanddecreasedTCRamRNAandsurfaceTCRexpressioninJurkat cells.However,lossofTCRexpressiontakesseveraldaysinthesecelllineexperiments.Inagreementwiththeseinvitro approaches, inducible deletion of Lat in vivo results in reduced TCRa mRNA- and surface TCR- expression in a delayed temporal manner as well. Lastly, we demonstrate that loss of basal LAT-RasGRP signals appears to lead to silencing or