NK and DC reciprocal interactions have only recently been investigated. In this study, we focused on the interplay between NK cells and DC in two models of bacterial infection. Immature monocyte-derived DC were cultured in the presence of live Escherichia coli or bacillus Calmette-Guérin. Upon exposure to either extracellular or intracellular bacteria, DC underwent maturation as assessed by the increased levels of expression of CD80,CD86, and HLA molecules and the de novo expression of CD83 and CCR7. Significant amounts of TNF-alpha and IL-12 were released by DC upon infection, whereas IL-2 and IL-15 were barely detectable in culture supernatants. Both infected and uninfected DC were capable of inducing in fresh autologous NK cells the expression of CD69 and HLA-DR and of inducing cell proliferation. Remarkably, however, infected DC were much stronger inducers of NK cell activation and proliferation than uninfected DC. Thus, after just 24 h of NK/DC coculture, only those NK cells that had been exposed to bacteria-infected DC had acquired the ability to lyse autologous immature DC. In addition, infected DC were more resistant to NK-mediated lysis as a consequence of the up-regulation of HLA class I molecule expression on their surface. This study suggests a regulatory circuit involving NK cells and DC in which DC-induced NK cell activation is effectively enhanced by the presence of pathogens. Activated NK cells, by limiting the supply of immature DC, may then exert a control on subsequent innate and adaptive immune responses.