Natural killer cell immune regulation: Coordination of immune function in tissues

Natural killer (NK) cells are potent effector cells of innate immunity. Their function is finely regulated by a series of activating and inhibitory receptors. Inhibitory receptors recognize MHC-class I molecules on potential target cells and prevent cellular activation and cytolysis when, they express sufficient amounts of MHC class I at their surface. A remarkable exception is represented by myeloid dendritic cells (DCs) that are killed by activated NK cells if they have failed to undergo complete maturation (DC editing). NK-DC interactions are greatly potentiated by pathogen-derived products that activate several different cell types of innate immunity through expression of Toll-like receptors (TLRs). Besides NK and DC, these cells include plasmacytoid DCs (PDCs), eosinophils and mast cells. The resulting crosstalk between these cell types is mediated by cytokines, chemokines or direct cell-to-cell interactions, so-called Signal 5s to distinguish them from the signals important in the afferent immune response. This crosstalk has a great impact not only on the quality and strength of innate immune responses but also on subsequent adaptive immune responses. Thus, NK cells play an important role in defence against pathogens (and tumor) not only because of their effector function but also because of their regulatory capability within tissues on the nature and quality of innate and adaptive immune responses. Classical innate effector cells can now be viewed also as regulatory cells that play a key role in defence against pathogens. Further understanding of the interaction within innate immunity and at the interface between innate and adaptive immunity should be of considerable aid in designing novel therapeutic strategies and effective vaccines against infectious agents and, perhaps, tumor.