Ligand interactions by activating and inhibitory Ly-49 receptors

Natural killer (NK) cells express families of homologous receptors, members of which either activate or inhibit NK cells. We demonstrate that mouse Ly-49D is an activating receptor for the MI-IC antigen H2-D-d, which is also a ligand for the related inhibitory receptor Ly-49A. To compare and contrast their interactions with class I MHC ligand, we studied each of these receptors expressed in a rat NK-cell line, RNK-16, for their capacity to recognize wild-type or mutated H2-D-d. Our studies with Ly-49A reveal that functional interaction with H2-D-d depends on residues in the floor of the H2-D-d peptide-binding groove. The recent co-crystal of Ly-49A with H2-D-d indicates that these are not contact residues, thus they may contribute to allelic specificity through conformational changes in H2-D-d. We found that structural requirements for functional recognition of H2-D-d by Ly-49D differ markedly from those for recognition by Ly-49A. We note that H2-D-d expression on certain target cells is not sufficient to activate lysis mediated by Ly-49D, though the additional requirements for functional interaction are not yet identified. Here we review recent studies of Ly-49 receptor ligand specificities and their molecular basis. The functions of these related receptors with opposing functions and shared allospecificity remains unclear.