LAUSR

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 (MHCIIlow) 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 MHCIIlow 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.