Revisiting human natural killer cell subset function revealed cytolytic CD56 ^dim CD16 ⁺ NK cells as rapid producers of abundant IFN-γ on activation

<jats:p> 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 <jats:sup>dim</jats:sup> CD16 <jats:sup>+</jats:sup> subset, whereas cytokine production is generally assigned to CD56 <jats:sup>bright</jats:sup> CD16 <jats:sup>+/−</jats:sup> cells. In this study, we reevaluated the functional capabilities of these NK subsets with regard to the production of IFN-γ 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 <jats:sup>dim</jats:sup> NK cells produce IFN-γ already at 2 to 4 h, whereas no cytokine production is detected beyond 16 h. In contrast, CD56 <jats:sup>bright</jats:sup> cells release IFN-γ only at late time intervals (>16 h after stimulation). The rapid IFN-γ production by CD56 <jats:sup>dim</jats:sup> NK cells is in line with the presence of IFN-γ mRNA in freshly isolated cells. Rapid IFN-γ 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-γ production is a functional property of CD56 <jats:sup>dim</jats:sup> NK cells. Thus, this subset can assure a rapid and comprehensive NK cell intervention during the early phases of innate responses. </jats:p>