NK Cell Terminal Differentiation Correlated Stepwise Decrease of NKG2A and Acquisition of KIRs 英文参考文献.docVIP

NKCellTerminalDifferentiation:CorrelatedStepwise DecreaseofNKG2AandAcquisitionofKIRs VivienBe′ziat1,2,BenjaminDescours1,2,ChristopheParizot3,PatriceDebre′1,2,3,VincentVieillard1,2 * 1INSERMUMR-S945,Ho?pitalPitie′-Salpe?trie`re, Paris,France,2Universite′ PierreetMarieCurie(Paris-6),Paris,France,3Laboratoired’ImmunologieCellulaireetTissulaire, Paris,France Abstract Background: Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminatingnormalcellsfromcellsindistress.AlthoughitiswellestablishedthatKIRs,inconjunctionwithNKG2A,playa majorroleintheNKcelleducationthatdetermines whethercellswillendupcompetentorhyporesponsive,theevents underlyingthedifferentiationarestilldebated. Methodology/PrincipalFindings:Acombinationofcomplementaryapproachestoassessthekineticsoftheappearanceof each subset during development allowed us to obtain new insights into these terminal stages of differentiation, characterising their gene expression profiles at a pan-genomic level, their distinct surface receptor patterns and their prototypic effector functions. The present study supports the hypothesis that CD56dim cells derive from the CD56bright subset and suggests that NK cell responsiveness is determined by persistent inhibitory signals received during their education. We report here the inverse correlation of NKG2A expression with KIR expression and explore whether this dim 2 + correlation bestows functional competence on NK cells. We show that CD56 NKG2A KIR cells display the most differentiatedphenotypeassociatedtotheiruniqueabilitytorespondagainstHLA-E+targetcells.Importantly,afterIL-12+ dim 2 IL-18stimulation,reacquisitionofNKG2AstronglycorrelateswithIFN-cproductioninCD56 NKG2A NKcells. Conclusions/Significance: Together, these findings call for the reclassification of mature human NK cells into distinct subsetsandsupportanewmodel,inwhichtheNKcelldifferentiationandfunctionalfatearebasedonastepwisedecrease ofNKG2Aandacquisi