Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages

Natural killer (NK) cells attack tumor and infected cells, but the receptor s and ligands that stimulate them are poorly understood. Here we report the expression cloning of two murine ligands for the lectin-like receptor NKG2 D. The two ligands, H-60 and Rae1 beta, are distant relatives of major hist ocompatibility complex class I molecules. NKG2D ligands are not expressed b y most normal cells but are up-regulated on numerous tumor cells. We show t hat mouse NKG2D is expressed by NK cells, activated CD8(+) T cells and acti vated macrophages. Expression of either NKG2D ligand by target cells trigge rs NK cell cytotoxicity and interferon-gamma secretion by NK cells, as well as nitric oxide release and tumor necrosis factor a transcription by macro phages. Thus, through their interaction with NKG2D, H-60 and Rae1 beta are newly identified potent stimulators of innate immunity.