Revisiting human natural killer cell subset function revealed cytolytic CD56dimCD16+ NK cells as rapid producers of abundant IFN-γ on activation

The two major functions of human natural killer (NK) cells are conventionally associated with distinct cell subsets. Thus, cytolytic activity is mostly confined to the CD56(dim)CD16(+) subset, whereas cytokine production is generally assigned to CD56(bright)CD16(+/-) cells. In this study, we reevaluated the functional capabilities of these NK subsets with regard to the production of IFN-gamma at different time points after cell triggering via NKp46 and NKp30 activating receptors. Different from previous studies, cytokine production was also assessed at early intervals. We show that CD56(dim) NK cells produce IFN-gamma already at 2 to 4 h, whereas no cytokine production is detected beyond 16 h. In contrast, CD56(bright) cells release IFN-gamma only at late time intervals (> 16 h after stimulation). The rapid IFN-gamma production by CD56(dim) NK cells is in line with the presence of IFN-gamma mRNA in freshly isolated cells. Rapid IFN-gamma production was also induced by combinations of IL-2, IL-12, and IL-15. Our data indicate that not only cytolytic activity but also early IFN-gamma production is a functional property of CD56(dim) NK cells. Thus, this subset can assure a rapid and comprehensive NK cell intervention during the early phases of innate responses.