Activation of dendritic cells (DCs) and macrophages by infectious agents leads to secretion of interleukin 12 (IL-12), which subsequently induces interferon-gamma (IFN-gamma) production by multiple cell types that include DCs and macrophages. In turn, IFN-gamma acts on macrophages to augment IL-12 secretion and to produce nitric oxide (NO), which eradicates infected microbes. We show here that in cytokine common gamma subunit-deficient and/or IL-2 receptor beta-deficient mice, production of IL-12, IFN-gamma and NO by DCs and macrophages was severely impaired, as was up-regulation of major histocompatibility complex class II and CD40. Similar phenotypes were observed in DCs and macrophages from IL-15-deficient mice but not in those from IL-2-deficient mice. This shows that the IL-15-IL-15R interaction is critical in early activation of antigen-presenting cells and plays an important role in the innate immune system.