Immune regulation by new NK receptor family molecules

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NK cell receptors consist of activating and inhibitory receptors. These receptors seem to have been evolved with pathogens such as viruses and seem to play an important role in host defense. In the present study, we have tried to elucidate the mechanism of immune regulation by NK cells through identification of new activating NK receptors and its ligands. We have identified activating PILR and CD200 receptors as DAP12 associating receptors from cDNA library of NK cells (Shiratori et al. J.Immunol. 2005). Furthermore, we have cloned the ligand for PILR and showed that PILR ligand play an important role for the target cell recognition by NK cells (Shiratori et al. J.Exp.Med. 2004). In addition, we have found that B16 melanoma is recognized by PILR although B16 does not express PILR-ligand. Therefore, we generated cDNA library from B16 melanoma and did expression cloning. We have cloned PILR-L2 as a ligand for PILR. Indeed, PILR-L2 expressing cells were recognized by PILR expressing cells. From these observations, PILR was found to play an important role in the target cell recognition by NK cells. Furthermore, we have found that glycosylation is involved in the ligand recognition by PILR. When certain glycosyltransferase was transfected to B16, PILR ligand exressed on B16 was not recognized by PILR anymore. PILR ligand expressed on B16 transfectants was not recognized by inhibitory PILR expressed on macrophage and B16 transfectants activated macrophage very well. Therefore, certain tumor cells seemed to have acquired the ligand for inhibitory PILR by modification of the structure of glycosylation of PILR ligand and seemed to suppress the response to tumor cells. These findings may provide a novel mechanism of immune evasion by tumor.