Activation of naïve NK cells in response to Listeria monocytogenes requires IL-18 and contact with infected dendritic cells1

摘要

The mechanisms for NK cell activation during infection by intracellular bacterial pathogens are not clearly defined. To dissect how Listeria monocytogenes infection elicits NK cell activation, we evaluated the requirements for activation of naïve splenic NK cells by infected bone marrow-derived dendritic cells (BMDC). We found that NK cell activation in this setting required infection of BMDC by live wild-type bacteria. NK cells were not activated when BMDC were infected with a live hemolysin deficient (Δhly) strain. Neutralization of IL-12, TNFα, or caspase-1 each dramatically reduced NK cell IFNγ production in response to live wt L. monocytogenes infection. Addition of recombinant IL-18, but not IL-1β, reversed the effects of caspase-1 inhibition. Recombinant IL-18 also restored NK cell activation by BMDC infected with Δhly L. monocytogenes, which produced IL-12 but not IL-18. IL-18 acted on NK cells, since MyD88 expression was required in responding NK cells, but not infected BMDC. However, secreted cytokines were not sufficient for activation of naïve NK cells by infected BMDC. Rather, NK cell activation additionally required contact between infected BMDC and NK cells. These data suggest that the activation of NK cells during L. monocytogenes infection requires both secreted cytokines and ligation of NK activating receptors during direct contact with infected DCs.