NK Cell Terminal Differentiation: Correlated Stepwise Decrease of NKG2A and Acquisition of KIRs

被引:163
作者
Beziat, Vivien [1 ,2 ]
Descours, Benjamin [1 ,2 ]
Parizot, Christophe [3 ]
Debre, Patrice [1 ,2 ,3 ]
Vieillard, Vincent [1 ,2 ]
机构
[1] Hop La Pitie Salpetriere, INSERM, UMR S 945, Paris, France
[2] Univ Paris 06, Paris, France
[3] Lab Immunol Cellulaire & Tissulaire, Paris, France
来源
PLOS ONE | 2010年 / 5卷 / 08期
关键词
HLA-E; INHIBITORY RECEPTORS; CD94/NKG2A; EXPRESSION; EDUCATION; INTERFACE; TOLERANCE; COMPLEX; INNATE; MHC;
D O I
10.1371/journal.pone.0011966
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminating normal cells from cells in distress. Although it is well established that KIRs, in conjunction with NKG2A, play a major role in the NK cell education that determines whether cells will end up competent or hyporesponsive, the events underlying the differentiation are still debated. Methodology/Principal Findings: A combination of complementary approaches to assess the kinetics of the appearance of 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 CD56(dim) cells derive from the CD56(bright) 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 correlation bestows functional competence on NK cells. We show that CD56(dim)NKG2A(-)KIR(+) cells display the most differentiated phenotype associated to their unique ability to respond against HLA-E+ target cells. Importantly, after IL-12 + IL-18 stimulation, reacquisition of NKG2A strongly correlates with IFN-gamma production in CD56(dim)NKG2A(-) NK cells. Conclusions/Significance: Together, these findings call for the reclassification of mature human NK cells into distinct subsets and support a new model, in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs.
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页数:12
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