Target Cell Recognition by Natural Killer Cells: The NKG2D Receptor-Ligand System

Natural killer (NK) cells are able to recognize and lyse transformed and infected cells. Until recently, NK cell recognition of target cells was considered to be largely “missing-self” recognition. Specifically, the primary function of NK cells was thought to be to attack cells that have downregulated self-MHC class I expression and spare normal class I cells. For this purpose NK cells express a variety of inhibitory receptors that recognize self-MHC class I molecules delivering an inhibitory signal to the NK cell. However, NK cells are able to efficiently attack some target cells that express normal levels of class I MHC molecules, while some other cells are not sensitive to NK cell-lysis despite low or absent class I MHC expression. These findings imply that stimulatory receptors and their ligands may play an important role in target cell recognition by NK cells. While stimulatory receptors expressed by NK cells have been identified over the years, the ligands for most of these receptors remain unknown.