Mouse Ly-49D Recognizes H-2D(d) and Activates Natural Killer Cell Cytotoxicity

Although activation of natural killer (NK) cytotoxicity is generally inhibited by target major histocompatibility complex (MHC) class I expression, subtle features of NK allorecognition suggest that NK cells possess receptors that are activated by target MHC I. The mouse Ly-49D receptor has been shown to activate NK cytotoxicity, although recognition of MHC class I has not been demonstrated previously. To define Ly-49D–ligand interactions, we transfected the mouse Ly-49D receptor into the rat NK line, RNK-16 (RNK.mLy-49D). As expected, anti– Ly-49D monoclonal antibody 12A8 specifically stimulated redirected lysis of the Fc receptor– bearing rat target YB2/0 by RNK.mLy-49D transfectants. RNK.mLy-49D effectors were tested against YB2/0 targets transfected with the mouse MHC I alleles H-2D(d), D(b), K(k), or K(b). RNK.mLy-49D cells lysed YB2/0.D(d) targets more efficiently than untransfected YB2/0 or YB2/0 transfected with D(b), K(k), or K(b). This augmented lysis of H-2D(d) targets was specifically inhibited by F(ab′)(2) anti–Ly-49D (12A8) and F(ab′)(2) anti–H-2D(d) (34-5-8S). RNK.mLy-49D effectors were also able to specifically lyse Concanavalin A blasts isolated from H-2(d) mice (BALB/c, B10.D2, and DBA/2) but not from H-2(b) or H-2(k) mice. These experiments show that the activating receptor Ly-49D specifically interacts with the MHC I antigen, H-2D(d), demonstrating the existence of alloactivating receptors on murine NK cells.