An Investigation of the Role of CD56bright Natural Killer Cells in an Inflammatory Response

Abstract

Natural killer (NK) cells are a distinct population of lymphocytes with powerful cytotoxic effects against virus infected cells and transformed cells, without the need for prior sensitisation. They play an important role in innate immunity, providing a first line of defence against invading pathogens and also play a part in initiating and influencing adaptive immunity. There are two major subsets of NK cells; CD56bright and CD56dim. The CD56dim subset are more proficient killers, whereas the CD56bight subset are more adept at producing cytokines. In the peripheral blood, the majority of NK cells are CD56dim. However, previous work has shown the converse to be true in the synovial fluid of joints that are inflamed in patients with rheumatoid arthritis and at other sites of peripheral inflammation including that involving pleural and peritoneal cavities; here ~90% of the NK cells are of the CD56bright phenotype. These synovial CD56bright NK cells can engage with CD14+ monocytes in a reciprocal activatory fashion, possibly contributing to the inflammatory state. The enrichment of CD56bright NK cells at sites of inflammation could reflect either preferential recruitment to the site of inflammation or local differentiation of the CD56dim to the CD56bright subset. This thesis addresses the mode of accumulation of CD56bright NK cells at sites of inflammation using an in vitro model. Trafficking of NK cells from the periphery to the site of inflammation involves transmigration across vascular endothelium, a process that has been shown to alter the phenotype and function of cells. This study provides novel evidence that the interaction of NK cells with endothelium results in the activation of NK cells and modifies the NK cell phenotype including the expression of certain adhesion molecules. Work presented in this study suggests that migration does not increase the functional capacities of NK cells but may to some degree maintain the capacity of NK cells to express interferon-γ and to degranulate. Furthermore, this thesis extends previous findings by examining the consequence of migration on NK cell interactions with macrophages and dendritic cells. The final results chapter in this study describes a population of CD56 negative CD16 expressing cells that share some characteristics with NK cells. This potentially novel subset of NK cells and has been described in several studies as being a dysfunctional. This thesis aims to provide data on the phenotype of these cells and to compare this with that of conventional NK cell subsets.