The Role of Activating Receptors in Natural Killer Cell Development

描述(申请人提供)：自然杀伤(NK)细胞是通过释放溶细胞颗粒或免疫刺激细胞因子来摧毁异常细胞(病毒感染或恶性细胞)的淋巴细胞。NK细胞在其细胞表面既表达激活受体又表达抑制受体。据认为，激活和抑制受体的信号平衡调节NK细胞。NK细胞发展其受体的机制现在开始被理解。我们的实验室最近证实，NK细胞表面抑制性Ly49受体与其发育早期的MHC I类配体的相互作用是NK细胞功能成熟的原因(称为许可)。这一事件很可能发生在NK细胞在骨髓中成熟时。在没有“许可”的情况下，NK细胞不能在靶细胞的刺激下进行强大的免疫反应。另一方面，人们对激活受体在NK细胞发育中的作用知之甚少。Ly49H受体是一种激活受体，在某些品系的小鼠NK细胞表面表达，对小鼠巨细胞病毒(MCMV)感染具有抵抗力。最近，该受体的配体已被确定为MCMV编码的蛋白M157。核心假设是M157的结构性表达将改变Ly49H+NK细胞的发育和/或功能。这项提议的目标是通过三个具体目标来检验这一假设。Aim 1的研究将确定在缺少Ly49H的情况下，病毒编码蛋白m157的表达是否会改变NK细胞的发育。这将通过在不表达Ly49H受体的品系中产生一只表达m157的转基因小鼠来实现。AIM2的研究将确定在Ly49H存在的情况下m157的表达是否会改变NK细胞的发育。这将通过将目标1中产生的小鼠与表达Ly49H的小鼠品系交配来完成。AIM 3中的研究将确定M157在骨髓外的表达是否通过以肝脏或肠道特异的方式表达mL57来改变NK细胞的发育和/或功能。自然杀伤(NK)细胞在病毒和肿瘤的免疫应答中发挥着重要作用。对NK细胞发展的洞察可能导致基于NK细胞的新疗法的产生，这种疗法可能被证明在病毒感染和癌症的治疗中有用。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are lymphocytes that destroy abnormal cells (virus infected or malignant cells) through the release of cytolytic granules or immune stimulatory cytokines. NK cells express both activating and inhibitory receptors on their cell surface. It is believed that a balance of signaling from both activating and inhibitory receptors regulates the NK cell. The mechanism by which NK cells develop their repertoire of receptors is now beginning to be understood. Our laboratory has recently demonstrated that the interaction of inhibitory Ly49 receptors on NK cells with their MHC class I ligands early in development is responsible for functional maturation of NK cells (termed "licensing"). This event likely takes place as the NK cell matures in the bone marrow. In the absence of "licensing", the NK cell fails to carry out a robust.immune responses upon stimulation by a target cell. On the other hand, little is known about the role of activating receptors in NK cell development. The Ly49H receptor is an activating receptor, expressed on the surface of NK cells in certain strains of mice, which confers resistance to murine cytomegalovirus (MCMV) infection. Recently, the ligand for this receptor has been identified as the MCMV-encoded protein m157. The core hypothesis is that the constitutive expression of m157 will alter the development and/or function of Ly49H+ NK cells. The goal of this proposal is to test this hypothesis via three specific aims. The studies in Aim 1 will determine if the expression of m157, a viral-encoded protein, will alter the development of NK cells in the absence of Ly49H. This will be accomplished by generating an m157-expressing transgenic mouse in a strain that does not express the Ly49H receptor. The studies in Aim2 will determine if expression of m157 in the presence of Ly49H will alter NK cell development. This will be accomplished by mating the mouse generated in Aim 1 with a strain of mouse that expresses Ly49H. The studies in Aim 3 will determine if the expression of m157 outside of the bone marrow alters NK cell development and/or function by expressing ml 57 in a liver-specific or intestine-specific fashion. Natural killer (NK) cells play an important role in the immune response to viruses and tumors. Insight into the development of NK cells could result in the generation of novel NK cell-based therapies that may prove useful in the treatment of viral infection and cancers.