Epigenetic regulation of IL‐12‐dependent T cell proliferation

[摘要] ItiswellestablishedthatthecytokineIL‐12andthetranscriptionfactorSTAT4,anessentialpartoftheIL‐12signalingpathway,arecriticalcomponentsoftheTh1differentiationprocessinTcells.Inresponsetopathogenicstimuli,thisprocesscausesTcellstoproliferaterapidlyandsecretehighamountsofthecytokineIFN‐γ,leadingtotheTh1proinflammatoryphenotype.However,therearestillunknowncomponentsofthisdifferentiationpathway.WeheredemonstratedthattheexpressionofthehistonemethyltransferaseMll1isdrivenbyIL‐12signalingthroughSTAT4inhumansandmiceandiscriticalfortheproperdifferentiationofanaϊveTcelltoaTh1cell.OnceMLL1isup‐regulatedbyIL‐12,itregulatestheproliferationofTh1cells.Asevidenceofthis,weshowthatTh1cellsfromMll1+/−miceareunabletoproliferaterapidlyinaTh1environmentinvitroandinvivo.Additionally,uponrestimulationwithcognateantigenMll1+/−,TcellsdonotconverttoaTh1phenotype,ascharacterizedbyIFN‐γoutput.Furthermore,weobservedareductioninIFN‐γproductionandproliferationinhumanperipheralbloodstimulatedwithtetanustoxoidbyuseofaspecificinhibitoroftheMLL1/menincomplex.Together,ourresultsdemonstratethattheMLL1geneplaysapreviouslyunrecognizedbutessentialroleinTh1cellbiologyandfurthermore,describesanovelpathwaythroughwhichMll1expressionisregulated...

[学科分类] 生理学

[关键词] trithorax;Th1 differentiation;histone methylation;STAT4