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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

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

DOI  :  10.1189/jlb.3A0315-135R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 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...

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