The cross-talk between DC and NK cells is relevant for immune responses to infectious agents and tumors. However, the molecular basis of such interaction was largely unknown. Here we defined the nature of the signals involved in DC-mediated NK cell activation, focusing on LPS stimulation, thereby mimicking the context of bacterial infections. NK cells were not able to directly sense LPS, but required TLR4-equipped accessory cells. We demonstrated that DC produce IL-2, IL-18 and IFN-β in response to LPS, and this is the minimal set of cytokines necessary and sufficient to activate NK cells in terms of IFN-γ release in vitro and in vivo. However, DC-derived IL-18 was released only in the presence of NK cells. Indeed, LPS stimulation alone was not able to trigger the secretion of IL-1 family members. In this respect, NK cells provided the inflammasome-activating signal required for full processing and secretion of IL-18. NK cell stimulatory capability seemed to be restricted to the CD8-negative DC subset. Differently from IFN-γ release, cytotoxic responses were enhanced only by IFN-β but not by IL-2 or IL-18.

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