SummaryAging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle-aged (18-60 years), old (60-80 years), and very old (80-100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR-1 ⁄ ILT-2 and high expression of both NKG2A and IFN-c. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56 bright subset, a specific increase in LIR-1 ⁄ ILT-2, and a perfect recovering of NK-cell function following IL2-activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging.

Human NK cells comprise two main subsets, CD56bright and CD56dim cells, which differ in function, phenotype, and tissue localization. To further dissect the differentiation from CD56bright to CD56dim cells, we performed ex vivo and in vitro experiments demonstrating that the CD56brightCD16+ cells are an intermediate stage of NK cell maturation. We observed that the maximal frequency of the CD56brightCD16+ subset among NK cells, following unrelated cord blood transplantation, occurs later than this of the CD56brightCD16− subset. We next performed an extensive phenotypic and functional analysis of CD56brightCD16+ cells in healthy donors, which displayed a phenotypic intermediary profile between CD56brightCD16− and CD56dimCD16+ NK cells. We also demonstrated that CD56brightCD16+ NK cells were fully able to kill target cells, both by Ab-dependent cell cytotoxicity (ADCC) and direct lysis, as compared with CD56brightCD16− cells. Importantly, in vitro differentiation experiments revealed that autologous T cells specifically encourage the differentiation from CD56brightCD16− to CD56brightCD16+ cells. Finally, further investigations performed in elderly patients clearly showed that both CD56brightCD16+ and CD56dimCD16+ mature subsets were substantially increased in older individuals, whereas the CD56brightCD16− precursor subset was decreased. Altogether, these data provide evidence that the CD56brightCD16+ NK cell subset is a functional intermediate between the CD56bright and CD56dim cells and is generated in the presence of autologous T CD3+ cells.