Immune regulation by new NK receptor family molecules

NK细胞受体包括激活受体和抑制受体。这些受体似乎是与病毒等病原体一起进化而来的，似乎在宿主防御中发挥着重要作用。在本研究中，我们试图通过鉴定新的激活NK受体及其配体来阐明NK细胞的免疫调节机制。我们已经从NK细胞的cDNA文库中鉴定出激活的PILR和CD200受体是DAP12相关受体(Shiratori et al.J.免疫。2005)。此外，我们已经克隆了PILR的配体，并表明PILR配体在NK细胞识别靶细胞方面发挥着重要作用(Shiratori等人)。J.Exp.Med。2004年)。此外，我们还发现，尽管B16不表达PILR配体，但B16黑色素瘤可以被PILR识别。因此，我们构建了B16黑色素瘤的cDNA文库，并进行了表达克隆。我们克隆了PILR-L2作为PILR的配体。事实上，表达PILR-L2的细胞能够被表达PILR的细胞识别。从这些观察中发现，PILR在NK细胞识别靶细胞的过程中起着重要作用。此外，我们还发现糖基化参与了PILR对配体的识别。当某些糖基转移酶被转入B16时，B16上的PILR配体不再被PILR识别。表达在B16细胞上的PILR配体不被表达在巨噬细胞上的PILR所识别，而表达在B16细胞上的PILR能很好地激活巨噬细胞。因此，某些肿瘤细胞似乎通过修饰PILR配体的糖基化结构而获得了抑制PILR的配体，并似乎抑制了对肿瘤细胞的反应。这些发现可能为肿瘤免疫逃逸提供一种新的机制。

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.