Dendritic cells Trigger IFN-γ secretion by NK cells independent of IL-12 and IL-18

It is commonly believed that IL-12 produced by DCs in response to pathogens is the first signal that stimulates the production of IFN-γ by NK cells. However, IL-12 production by DCs in response to bacterial LPS depends on either engagement of CD40 by CD40L on activated T cells or IFN-γ from NK cells. This suggests that during the primary immune response, NK cells produce IFN-γ before IL-12 production by DCs. Here, using single-cell measurements, cell sorting and mouse lines deficient in IL-12, IL-23, type I IFN receptor and the IL-18 receptor, we show that a subset of BM-derived DCs characterized by low expression of MHC class II (MHCII^low ) stimulates IFN-γ production by NK cells. The expression of Toll-like Receptor (TLR) 4 on DCs but not NK cells was required for such NK-derived IFN-γ. In addition, soluble factor(s) produced by LPS-activated MHCII^low DCs were sufficient to induce IFN-γ production by NK cells independent of IL-12, IL-23, and IL-18. This response was enhanced in the presence of a low dose of IL-2. These results delineate a previously unknown pathway of DC-mediated IFN-γ production by NK cells, which is independent of commonly known cytokines.