CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells

Human natural killer (NK) cells comprise 2 main subsets, CD56 bright and CD56dim cells, that differ in function, phenotype, and tissue localization. To further dissect the heterogeneity of CD56dim cells, we have performed transcriptome analysis and functional ex vivo characterization of human NK-cell subsets according to the expression of markers related to differentiation, migration or competence. Here, we show for the first time that the ability to respond to cytokines or to activating receptors is mutually exclusive in almost all NK cells with the exception of CD56dim CD62L+ cells. Indeed, only these cells combine the ability to produce interferon-γ after cytokines and proliferate in vivo during viral infection with the capacity to kill and produce cytokines upon engagement of activating receptors. Therefore, CD56 dim CD62L+ cells represent a unique subset of polyfunctional NK cells. Ex vivo analysis of their function, phenotype, telomere length, frequencies during ageing as well as transfer experiments of NK-cell subsets into immunodeficient mice suggest that CD56dim CD62L + cells represent an intermediate stage of NK-cell maturation, which after restimulation can accomplish multiple tasks and further develop into terminally differentiated effectors. © 2010 by The American Society of Hematology.