Specificity and function of activating Ly-49 receptors

Inhibitory Ly‐49 receptors allow murine natural killer (NK) cells to kill cells with aberrant class I MHC expression while sparing normal cells. This is accomplished by their recognition of specific class I MHC products and prevention of NK‐cell lysis of cells that present a normal repertoire of class I MHC ligands –“the missing self hypothesis”. However, Ly‐49 receptors that lack the cytoplasmic immunoreceptor tyrosine‐based inhibitory motif, which is required for inhibition of killing, have also been described. These receptors were found to stimulate NK killing and are therefore referred to as activating Ly‐49 receptors. Interestingly, the activating receptors have class I MHC‐binding domains that are nearly indistinguishable from those of the inhibiting receptors, and binding to class I MHC has now been demonstrated for three activating receptors. Presently, there is no defined physiological role for activating Ly‐49 receptors. Here we present an overview of current knowledge regarding the diversity, structure and function of activating Ly‐49 receptors with a focus on class I MHC specificity, and we discuss their potential role(s) in natural resistance. This research was supported by an operating grant from the National Cancer Institute of Canada and the Canadian Cancer Society (K. P. Kane) and a Canadian Institutes for Health Research operating grant (B. Hazes). E. Silver is supported by an Alberta Heritage Foundation for Medical Research (AHFMR) studentship and K. P. Kane is an (AHFMR) senior scholar.