A novel ligand for the NKG2D receptor activates NK cells and macrophages and induces tumor immunity

NK cells are involved in the immune response against viral and microbial infections and tumors. In contrast to B and T cells, NK cells employ various modes of immune recognition. An important mode of immune recognition employed by NK cells is induced self recognition exemplified by the NKG2D receptor-ligand system. The NKG2D immunoreceptor, expressed by NK cells, and by activated CD8(+) T cells and macrophages, recognizes one of several cell surface ligands that are distantly related to MHC class I molecules (i.e. H60 and Rae1 proteins in mice, and MHC class I chain-related proteins and UL-16-binding proteins in humans). These ligands are not expressed abundantly by most normal cells but are upregulated on cells exposed to various forms of cellular insults. Here we report the cloning of another ligand for NKG2D; transcripts of this ligand are found in a wide variety of tissues and in various tumor cells. Cross-linking of NKG2D with the novel ligand potently activated NK cells and macrophages. Tumor cells ectopically expressing the molecule were efficiently rejected by naive mice, and induced strong protective immunity to the parental, ligand-negative tumor cells.