Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity

Natural killer (NK) cells attack many tumour cell lines, and are thought to have a critical role in anti-tumour immunity(1-7); however, the interactio n between NK cells and tumour targets is poorly understood. The stimulatory lectin-like NKG2D receptor(8-13) is expressed by NK cells, activated CD8() T cells and by activated macrophages in mice(11). Several distinct cell-s urface ligands that are related to class I major histocompatibility complex molecules have been identified(11-14), some of which are expressed at high levels by tumour cells but not by normal cells in adults(11,13,15,16). How ever, no direct evidence links the expression of these 'induced self' ligan ds with tumour cell rejection. Here we demonstrate that ectopic expression of the murine NKG2D ligands Rae1 beta or H60 in several tumour cell lines r esults in potent rejection of the tumour cells by syngeneic mice. Rejection is mediated by NK cells and/or CD8(+) T cells. The ligand-expressing tumou r cells induce potent priming of cytotoxic T cells and sensitization of NK cells in vivo. Mice that are exposed to live or irradiated tumour cells exp ressing Rae1 beta or H60 are specifically immune to subsequent challenge wi th tumour cells that lack NKG2D ligands, suggesting application of the liga nds in the design of tumour vaccines.