Defining the functional role of CD56 on human natural killer cells

项目摘要 人类自然杀伤（NK）细胞对于控制病毒感染和它们对肿瘤的重要性至关重要 它们作为癌症免疫工具的新用途强调了监测。理解独特 人类NK细胞未被小鼠NK细胞生物学发现的方面对于推进我们的研究至关重要。 NK细胞在免疫治疗中的应用CD 56是糖蛋白神经细胞粘附分子（NCAM）， 在人而非小鼠NK细胞上普遍表达。部分是因为它独特的人类表达方式， CD 56/NCAM在免疫细胞中的分子功能尚未阐明。我们的初步数据显示 CD 56/NCAM在人类NK细胞上起着功能性作用，并表明了独特的CD 56/NCAM的关键方面。 生物学决定了它的功能。为了描述这一功能，我们将仔细研究以下三个方面： CD 56/NCAM在三个独立的目标中起作用。目标1将确定添加以下物质的功能效果 聚唾液酸对CD 56/NCAM的作用以及聚唾液酸的空间性质对膜的作用 CD 56/NCAM和其它NK细胞活化受体和整合素的扩散。目标2将确定联系 CD 56/NCAM和NK细胞骨架之间的关系，包括描绘CD 56和肌动蛋白之间的联系。 目的3：鉴定CD 56/NCAM的细胞内结合伴侣，并确定脂筏在CD 56/NCAM细胞内的作用。 招募在其信号和功能中发挥作用。总之，这些目标将描绘这一功能， 在人类NK细胞上普遍表达但知之甚少的受体。它还将提供关键的洞察力 CD 56/NCAM和糖蛋白在决定关键的NK细胞中发挥的功能作用 功能包括细胞迁移和靶细胞杀伤。

Project summary Human natural killer (NK) cells are critical for control of viral infection and their importance for tumor surveillance is underscored by their emerging use as a cancer immunotherapeutic tool. Understanding unique aspects of human NK cells that are not uncovered by the biology of murine NK cells is critical to advancing our use of NK cells in immunotherapy. CD56, which is the glycoprotein neural cell adhesion molecule (NCAM), is ubiquitously expressed on human, but not mouse, NK cells. In part because of its uniquely human expression, the molecular function of CD56/NCAM has not elucidated on immune cells. Our preliminary data demonstrates that CD56/NCAM plays a functional role on human NK cells and indicates key aspects of unique CD56/NCAM biology that dictate its function. To delineate this function, we will closely examine three aspects of CD56/NCAM function in three independent aims. Aim 1 will determine the functional effect of the addition of polysialic acid to CD56/NCAM and the role that the steric properties of polysialic acid have on the membrane diffusion of CD56/NCAM and other NK cell activating receptors and integrins. Aim 2 will define the linkage between CD56/NCAM and the NK cell cytoskeleton, including delineating the link between CD56 and actin. Aim 3 will identify intracellular binding partners of CD56/NCAM and determine the role that lipid raft recruitment plays in its signaling and function. Together, these aims will delineate the function of this universally expressed and but poorly understood receptor on human NK cells. It will also provide critical insight into the functional role that CD56/NCAM, and glycoproteins in general, play in dictating critical NK cell functions including cell migration and target cell killing.