Ligands for natural killer cell receptors: redundancy or specificity

Several inhibitory and activating receptors involved in natural killer cell activation have been characterized. The increasing knowledge about their ligands, including classical MHC class I molecules, non-classical MHC class I molecules and MHC class I-related molecules, is shedding new light on the targets of innate immune recognition. While classical MHC class I molecules are constitutively expressed, some MHC class I-related (MIC) molecules, however, are stress-induced by ill-defined stimuli. Two families of ligands for the human activating NKG2D receptor have been identified. These are the MIC proteins encoded by two highly polymorphic genes within the MHC class I and the retinoic acid-inducible early gene-1-like (also designated UL16-binding) proteins encoded by genes outside the MHC. For the mouse NKG2D receptor, one family, containing at least five distinct ligands, has been described. A better understanding about how targets signal their distress, which renders them susceptible to natural killer (NK)-cell attack, will help to define the role of NK cells in antimicrobial and antitumor immunity and transplantation.