Ligand interactions by activating and inhibitory Ly‐49 receptors

Summary: 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 MHC 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. This work was supported by the Veterans Administration. M.C.N. is also supported by the Arthritis Foundation and the American Cancer Society. W.E.S. received NIH grant RO1 CA69299. We thank J.C. Ryan for communication of unpublished results. We thank H. Houtkooper and T. Ferrin for the molecular graphics image in Fig. 3 , which was created with the MidasPlus modeling system, supported by the NIH grant P41‐RR‐01081.