Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: the case of IL-27

Natural killer (NK) cells are characterized by their ability to detect and induce apoptosis of susceptible target cells and by the secretion of immunoregulatory cytokines such as IFN-gamma. The activation of these effector functions is triggered upon recognition of tumor and pathogen (mostly virus)-infected cells and as a consequence of a bidirectional crosstalk that NK cells establish with other cells of myeloid origin such as dendritic cells (DC) and macrophages. A common characteristic of these myeloid cells is their ability to secrete different members of the IL-12 family of cytokines such as IL-12, IL-23 and IL-27, and cytokines such as IL-15 and IL-18. Although the effect of IL-12, IL-15 and IL-18 has been characterized, the effect of IL-23 and IL-27 on NK cells (especially human), remains ill-defined. Particularly, IL-27 is a cytokine with dual functions as it has been described as pro- and as anti-inflammatory in different experimental settings. However, recent evidence indicates that this cytokine indeed promotes human NK cell activation, IFN- secretion, NKp46-dependent NK cell-mediated cytotoxicity and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC) against monoclonal Ab (mAb)-coated tumor cells. Remarkably, IL-27 also primes NK cells for IL-18 responsiveness, enhancing these functional responses. Consequently, IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions, which likely contributes to foster the adaptive immune response in different physiopathological conditions.