The tryptophan metabolite picolinic acid suppresses proliferation and metabolic activity of CD4+ T cells and inhibits c‐Myc activation

[摘要] Tryptophanmetabolites,includingkynurenine,3‐hydroxyanthranilicacid,andpicolinicacid,arekeymediatorsofimmunosuppressionbycellsexpressingthetryptophan‐catabolizingenzymeindoleamine2,3‐dioxygenase.Inthisstudy,weassessedtheinfluenceofpicolinicacidoncellviabilityandeffectorfunctionsofCD4+Tcellsfollowinginvitroactivationwithagonisticanti‐CD3/anti‐CD28antibodies.Incontrasttokynurenineand3‐hydroxyanthranilicacid,exposureofTcellswithpicolinicaciddidnotaffectcellviability,whereasproliferationandmetabolicactivityweresuppressedinadose‐dependentmanner.Ontheotherhand,cytokinesecretionandup‐regulationofcellsurfaceactivationmarkerswerenotoronlyweaklyinhibitedbypicolinicacid.PicolinicacidexposureinducedastateofdeepanergythatcouldnotbeovercomebytheadditionofexogenousIL‐2andinhibitedThcellpolarization.Onthemolecularlevel,importantupstreamsignalingmolecules,suchastheMAPKsERKandp38andthemammaliantargetofrapamycintargetproteinS6ribosomalprotein,werenotaffectedbypicolinicacid.Likewise,NFAT,NF‐κB,andAP‐1promoteractivityinJurkatTcellswasnotinfluencedbyexposuretopicolinicacid.Whereastranscriptionallevelsofv‐mycavianmyelocytomatosisviraloncogenehomologwerenotaffectedbypicolinicacid,phosphorylationatSer62wasstronglyreducedinpicolinicacid‐exposedTcellsfollowingactivation.Inconclusion,picolinicacidmediatesauniqueimmunosuppressiveprograminTcells,mainlyinhibitingcellcycleandmetabolicactivity,whileleavingothereffectorfunctionsintact.Thesefunctionalfeaturesareaccompaniedbyreducedphosphorylationofv‐mycavianmyelocytomatosisviraloncogenehomolog.ItremainstobedeterminedwhetherthiseffectismediatedbydirectinhibitionofERKactivityorwhetherindirectmechanismsapply...

[学科分类] 生理学

[关键词] immunosuppression;immune tolerance;anergy;indoleamine 2,3‐dioxygenase