Determinants of Natural Killer Cell Ly49 Receptor Specificity

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Natural killer (NK) cells are lymphocytes that act as a first line of defense against viruses and tumours, destroying pathologically altered cells. NK cells express inhibitory receptors specific for class I (CI) major histocompatiblity complex molecules ubiquitously expressed on healthy cells. Lack of engagement of NK inhibitory receptors, due to loss of CI expression that typically occurs with virus-infected cells or tumour cells, releases inhibition of NK cells, allowing them to destroy such altered cells. Ly49 are large families of major class of CI-specific receptors expressed by mouse and rat NK cells, but not humans. CI associate with beta-2 microglobulin (b2m) and bind and present peptide fragments from intracellular proteolytic events. We, and others, have found that the identity of the CI-bound peptide can determine Ly49 recognition of CI. What is unclear, is the nature of endogenous peptides in healthy cells that regulate NK cells, and the