Defining the functional role of CD56 on human natural killer cells

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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.