NK cells are believed to play a mandatory role during the early phases of Listeria monocytogenes infection by producing IFN-gamma, which is required for the activation of macrophage effector functions. Mice deficient in the common cytokine receptor gamma-chain (gamma(c)-/-), which completely lack NK cells, were used to examine whether NK cells were essential for resistance to Listeria infection in vivo. Surprisingly, infected gamma(c)-/- mice showed normal innate immunity and macrophage responses against sublethal Listeria infection 2 days postinfection. At this time point, gamma(c)-/- mice showed increased blood IFN-gamma levels compared with those in noninfected controls, demonstrating an NK-independent source of IFN-gamma, which explains early resistance. Listeria-infected gamma(c)-/- x recombinase-activating gene-2-/- double-deficient mice were unable to produce IFN-gamma and were highly susceptible to L. monocytogenes. Since T cells, but not B cells, are major IFN-gamma producers, and gamma(c)-/- T cells were found to be efficient IFN-gamma producers in vitro, we conclude from these results that T cells functionally replace NK cells for the early IFN-gamma production that is necessary for activating the innate immune system following infection with L. monocytogenes. This novel observation in listeriosis underscores how the adaptive immune response can maintain and influence innate immunity.