Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses

Abstract

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...

Activin-A attenuates several human natural killer cell functions

“…12,45 These ligands are known to stimulate pDCs to produce large amounts of type I interferons, which enhance very early activation of NK cells. 48,49 Thus, pDCs potentially do not possess this mechanism of NK-cell regulation, and this finding highlights that interactions between pDCs and NK cells may be qualitatively different to those of other DC subsets.…”

NK cells at the interface between innate and adaptive immunity

“…In turn, NK cells promote PDC maturation and upregulate their production of IFN-a in response to CpG. 22,78 Interestingly, while NK cells cannot exert an editing program on PDCs due to the poor susceptibility of these cells to NK-mediated lysis, when co-cultured with TLR9-stimulated PDCs, NK cells acquire lytic activity against immature DCs. Thus, it is possible that cellular interactions occurring between NK and PDCs in response to TLR9 stimulation may influence the maturation and acquisition of functional competence by bystander DCs.…”

“…These data suggest that a multidirectional PDC-NK-DC crosstalk may deeply affect the outcome of antiviral and anti-tumor immunity by regulating both innate NK cell responses and Th polarization. 78 The molecular interactions regulating the cross talk between NK and monocyte-derived DCs might change at least in part when DCs are subjected to viral infection. In this context a recent study by Draghi et al 79 analyzed the impact of influenza-infected human DCs on NK cell activation.…”

Psychological stress exacerbates primary vaginal herpes simplex virus type 1 (HSV-1) infection by impairing both innate and adaptive immune responses

“…For example, activated NK cells induce DC maturation (Vitale et al, 2005), increase IFN-α and IL-6 production by plasmacytoid DC (Della Chiesa et al, 2006), and increase CD80 expression by myeloid-derived DC (Gerosa et al, 2005). Therefore, reduced NK cell numbers may impair DC-priming of naive T cells, thus indirectly contributing to an impaired cell-mediated immune response.…”