During innate immune responses, natural killer (NK) cells may interact with both plasmacytoid dendritic cells (pDCs) and monocyte-derived dendritic cells (MDDCs). We show that freshly isolated NK cells promote the release by pDCs of IFN-␣, in a CpG-dependent manner, whereas they induce IL-6 production in a CpG-independent manner. In turn pDCderived IFN-␣ up-regulates NK-mediated killing, whereas IL-6 could promote B-cell differentiation. We also show that expo-
IntroductionInnate immune responses play a crucial role not only in controlling pathogen invasion, but also in instructing the adaptive immune system to initiate a specific response against infecting pathogens. 1 Natural killer (NK) cells and dendritic cells (DCs) represent crucial effector cells of the innate immune system. 2,3 Several reports have highlighted the importance of the reciprocal interaction between NK cells and DCs during the early stages of innate immune responses. [4][5][6][7][8][9] The NK/DC cross talk can occur within inflamed peripheral tissues and results in a potent DC-induced activation of NK-cell functions, which, in turn, exert a modulatory role on DC activity. Pathogen clearance mediated by innate effector mechanisms is, at least in part, the result of the DC-induced up-regulation of NK-cell cytotoxicity and of the release of antimicrobial cytokines from various cell types recruited at the inflammatory sites. 10,11 The reciprocal interactions between NK and DCs could regulate the quality of DCs undergoing maturation. For example, because NK cells are capable of killing immature DC (iDCs), the existence of an "editing" process has been suggested, by which DCs may or may not acquire the ability to prime Th1 immune responses. 12,13 Most reports regarding the cross talk between NK cells and DCs in humans have been focused on the interactions with monocyte-derived dendritic cells (MDDCs), whereas only limited information exists on the interaction with plasmacytoid DCs (pDCs). 14,15 pDCs are capable of producing large amounts of IFN-␣ in response to viral DNA or RNA. 16 This suggests that, together with NK cells, they play an important role in sensing viral infections and in promoting antiviral innate responses. We have previously shown that pDCs, on stimulation through TLR9, can activate NK cells to kill various types of tumor cells. Moreover, following TLR9 engagement, pDCs could induce a selective proliferation of the small NK-cell subset characterized by the CD56 bright phenotype. 15 In addition, IL-2-activated NK cells have been shown to promote pDC maturation and IFN-␣ release. 14 On the other hand, it is not clear whether, in humans, this event can actually occur during the early phases of innate immune responses in which T cells (ie, the only IL-2-producing cells) are not involved.In the present study we show that the regulatory effect of NK cells on pDC function does not strictly require exposure to IL-2, because also freshly isolated NK cells promoted pDC maturation and cytokine release. Moreover, an abundant IFN-␣ release b...