Natural killer T cell subsets and regulation of autoimmune diabetes

Abstract: This thesis is focused on natural killer (NK) T cells. NKT cells recognize lipids and glycolipids, rather than peptides, in the contents of the antigen presenting molecule CD1d. NKT cells have a surface phenotype reminiscent of memory cells, and have been shown to rapidly produce large amounts of cytokines, such as IL-4 and IFN-gamma, upon activation. Because of their rapid response to activation, NKT cells have been suggested to play a role in several different immunological situations, such as clearance of pathogens, tumor rejection and regulation of autoimmune reactions. The broad spectrum of their activities suggested that functionally different subsets of NKT cells might exist. We have been able to demonstrate two functionally distinct splenic NKT cell populations identified by their surface phenotype and cytokine secretion profile. Previous reports of reduced autoimmune diabetes incidence in NOD mice related to an artificially increased NKT cell population have been attributed to the enhanced production of IL-4 by classical NKT cells. We show that an overexpression in NOD mice of non-classical NKT cells, producing high levels of IFN-gamma but low amounts of IL-4, leads to prevention of autoimmune diabetes. This demonstrates that both classical and non-classical NKT cells possess immuno-regulatory functions. Finding out which mechanisms that are shared by all NKT cells and which that are not, will broaden our knowledge on NKT cell biology and increase the possibility to control the immune system in a way that may prevent diseases and autoimmunity.