Evidence Implicating the Ras Pathway in Multiple CD28 Costimulatory Functions in CD4+ T Cells 英文参考文献.docVIP

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Evidence Implicating the Ras Pathway in Multiple CD28 Costimulatory Functions in CD4+ T Cells 英文参考文献.doc

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EvidenceImplicatingtheRasPathwayinMultipleCD28CostimulatoryFunctionsinCD4TCells英文参考文献

EvidenceImplicatingtheRasPathwayinMultipleCD28 CostimulatoryFunctionsinCD4 TCells + SujitV.Janardhan1,KesavannairPraveen1,ReinhardMarks1,ThomasF.Gajewski1,2* 1DepartmentofPathology,TheUniversityofChicago,Chicago,Illinois,UnitedStatesofAmerica,2DepartmentofMedicine,TheUniversityofChicago,Chicago,Illinois, UnitedStatesofAmerica Abstract CD28 costimulation is a critical event in the full activation of CD4+ T cells that augments cytokine gene transcription, promotescytokinemRNAstability,preventsinductionofanergy,increasescellularmetabolism,andincreasescellsurvival. However, despite extensive biochemical analysis of the signaling events downstream of CD28, molecular pathways sufficient to functionally replace the diverse aspects of CD28-mediated costimulation in normal T cells have not been identified.Ras/MAPKsignalingisacriticalpathwaydownstreamofTcellreceptorstimulation,butitsroleinCD28-mediated costimulation has been controversial. We observed that physiologic CD28 costimulation caused a relocalization of the RasGEFRasGRPtotheTcell-APCinterfacebyconfocalmicroscopy.Inwholecellbiochemicalanalysis,CD28cross-linking witheitheranti-CD28antibodyorB7.1-IgaugmentedTCR-inducedRasactivation.TodeterminewhetherRassignalingwas sufficienttofunctionallymimicCD28costimulation,weutilizedanadenoviralvectorencodingconstitutivelyactiveH-Ras + (61L)totransducenormal,Coxsackie-AdenovirusReceptor(CAR)transgenicCD4 Tcells.LikecostimulationviaCD28,active Ras induced AKT, JNK and ERK phosphorylation. In addition, constitutive Ras signaling mimicked the ability of CD28 to costimulate IL-2 protein secretion, prevent anergy induction, increase glucose uptake, and promote cell survival. Importantly, we also found that active Ras mimicked the mechanism by which CD28 costimulates IL-2 production: by increasingIL-2genetranscription,andpromotingIL-2mRNAstability.Finally,activeRaswasabletoinduceIL-2production whencombinedwithionomycinstimulationinaMEK-1-dependentfashion.Ourresultsareconsistentwi