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

Natural killer (NK) cells express a superfamily of surface proteins that share 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 encompasses several families of genes including NKR-PI, Ly-49, CD94/NKG2, and NKG2D. Different NKC-encoded receptors have been shown to activate or to inhibit NK-cell function, and different receptors within the same family can have opposing functions. Within an individual NK cell, inhibitory receptors typically predominate over stimulatory receptors, calling into question the teleologic requirement or physiologic significance of lectin-like activating receptors in NK cells. Despite the widespread expression of inhibitory receptors, however, subtle features of activating receptor biology enable them to stimulate effector functions in vivo and in vitro. Activating receptors and inhibitory receptors differ in their subset expression, in their structural constraints for binding to common ligands, in their ligand repertoires, and in that divergent families of activating receptors utilize different signaling pathways. These subset, binding, repertoire, and signaling diversities may allow activating receptors to manifest their effects in spite of inhibitory receptor functions during pathologic conditions in vivo. In this review, we will present a detailed analysis of the data supporting this hypothesis with particular relevance toward physiologic NK-cell functions.