This study investigates the reciprocal activating interaction between human peripheral blood natural killer (NK) cells and monocyte-derived immature dendritic cells (DC). Fresh NK cells, when activated by IL-2, exhibit increased cytotoxic activity against target cells, particularly when co-cultured with mature DC treated with lipopolysaccharide (LPS), Mycobacterium tuberculosis, or interferon (IFN)-α. Conversely, NK cells cultured with immature DC in the presence of maturation stimuli strongly enhance DC maturation and interleukin (IL)-12 production. IL-2-activated NK cells directly induce DC maturation and enhance their ability to stimulate allogeneic naive CD4+ T cells. The effects are cell contact-dependent, although the secretion of IFN-γ and TNF also contributes to DC maturation. Within peripheral blood lymphocytes, the reciprocal activating interaction with DC is restricted to NK cells, as other lymphocyte subsets do not exhibit similar responses. These findings demonstrate a bidirectional cross talk between NK cells and DC, where both cell types are activated and mature through each other.This study investigates the reciprocal activating interaction between human peripheral blood natural killer (NK) cells and monocyte-derived immature dendritic cells (DC). Fresh NK cells, when activated by IL-2, exhibit increased cytotoxic activity against target cells, particularly when co-cultured with mature DC treated with lipopolysaccharide (LPS), Mycobacterium tuberculosis, or interferon (IFN)-α. Conversely, NK cells cultured with immature DC in the presence of maturation stimuli strongly enhance DC maturation and interleukin (IL)-12 production. IL-2-activated NK cells directly induce DC maturation and enhance their ability to stimulate allogeneic naive CD4+ T cells. The effects are cell contact-dependent, although the secretion of IFN-γ and TNF also contributes to DC maturation. Within peripheral blood lymphocytes, the reciprocal activating interaction with DC is restricted to NK cells, as other lymphocyte subsets do not exhibit similar responses. These findings demonstrate a bidirectional cross talk between NK cells and DC, where both cell types are activated and mature through each other.