Physiologic functions of activating natural killer (NK) complex-encoded receptors on NK cells

Natural killer (NK) cells express a. superfamily of surface proteins that s hare common structural features: dimeric type II integral membrane proteins with extracellular domains resembling C-type lectins. These receptors are encoded by a single genetic region called the NK complex (NKC). The NKC enc ompasses several families of genes including NKR-P1, Ly-49, CD94/NKG2, and NKG2D. Different NKC-encoded receptors have been shown to activate or to in hibit NK-cell function, and different receptors within the same, family can have opposing functions. Within an individual NK cell, inhibitory receptor s typically predominate over stimulatory receptors, calling into question t he teleologic requirement or physiologic significance of lectin-like activa ting receptors in NK cells. Despite the widespread expression of inhibitory receptors, however subtle features of activating receptor biology enable t hem to stimulate effector functions in vivo and in vitro. Activating recept ors and inhibitory receptors differ in their subset expression, in their st ructural constraints for binding to common ligands in their ligand repertoi res, and in that divergent families of activating receptors utilize differe nt signaling pathways. These subset, binding, repertoire, and signaling div ersities may allow activating receptors to manifest their effects in spite of inhibitory receptor functions during pathologic conditions in vivo. In t his review, we will present a detailed analysis of the data supporting this hypothesis with particular relevance toward physiologic NK-cell functions.