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As the molecular networks that connect innate and adaptive immunity are untangled, the prominence of natural killer (NK) cells in host defense continues to emerge. Herein we highlight recent findings pertaining to NK cell development, trafficking, and interactions with other innate and adaptive immune cells in the context of predicting how NK cells may be involved in a wider range of clinical immunodeficiency.NK cells contribute vital roles in innate and adaptive immunity, especially in collaboration with dendritic cells (DC). Fascinating new details have been reported about cell surface integrins and receptors that regulate NK functions, as well as the cytokine/chemokine networks that provide for NK–DC interactions. Moreover, NK cells appear to play an important role in the attenuation or resolution of an immune response through either action against CD8 T cells or indirect control of certain DC. These findings shed important insights as to how NK cells and DC cooperate to control primary infections and shape the subsequent adaptive immune responses.Natural killer cells are heterogeneous lymphocytes that provide an essential function in host defense. NK cells respond early to microbial assault and interact with other cells of the innate immune system, but they recognize and intercept pathogenic infections through highly specific mechanisms that are similar to T cells. Thus, NK cells are positioned as a cellular bridge between innate and adaptive immunity. It is imperative, then, to include a careful assessment of NK cell populations and functions in most cases of suspected immunodeficiency.