Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression

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

关键词: NKG2D;    NKp46;    cytokines;    cytotoxicity;   

DOI  :  10.1189/jlb.0711339

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

HDACiarebeingusedasanovel,therapeuticapproachforleukemiasandotherhematologicalmalignancies.However,theireffectonimmunecellsremainsill‐defined,asHDACimayimpairimmunesurveillance.Inthiswork,wedemonstratethatTSA,VPA,andNaBinhibitedIFN‐γproductionbyCD56dimandCD56brightNKcellsandNKcell‐mediatedcytotoxicityagainstK562targetcells.HDACipromotedminorNKcellapoptosisbutinhibitednuclearmobilizationofNF‐κBp50,whichwasaccompaniedbyarobustdown‐regulationofNKG2DandNKp46onrestingNKcellsandofNKG2D,NKp44,NKp46,andCD25oncytokine‐activatedNKcells.DecreasedCD25expressionpromotedaweakenedIFN‐γsecretionuponrestimulationofNKcellswithIL‐2,whereasreducedexpressionofNKG2DandNKp46wasaccompaniedbyanimpairedNKG2D‐andNKp46‐dependentcytotoxicity.Moreover,NKcellsfromnormalmicetreatedinvivowithTSAdisplayedadiminishedexpressionofNK1.1,NKG2D,andNKp46andsecretedreducedamountsofIFN‐γuponexvivostimulationwithcytokines.Thus,ourpreclinicalresultsindicatethatHDACiexertdeleteriouseffectsonNKcellfunction,whichmayweakenimmunesurveillanceandfacilitaterelapseofthemalignantdiseaseinHDACi‐treatedpatients...

【 授权许可】

CC BY