Natural killer T cells (NKT cells) play an important role in regulating immune responses. NKT cells arestimulate by glycolipid antigens presented by CD1d, and in the last few years significant advances havebeen made in understanding this process. Natural antigens for NKT cells have been identified, and crystalstructures of CD1d bound to glycolipids have been solved. As factors leading to NKT cell stimulation areelucidated, the importance of glycolipid trafficking and specific interactions with T cell receptors (TCRs) isemerging. However, glycolipid trafficking and interactions with TCRs are not well understood. Proposedresearch includes development of labeled glycolipids for use in studying specific trafficking events;specifically, the influences of structural variations of glycolipids on trafficking and how differences intrafficking influence the Th1/Th2 bias of cytokine release by NKT cells. Studies of glycolipid and CD1dinteractions with TCRs will involve incremental structural modifications of known antigens to determinerequirements for association and stimulation. In addition, glycolipid functionality has bee identified that canbe modified without impacting negatively NKT cell stimulation, and this information provides a means ofusing small molecules appended to glycolipids to modify the affinity of TCRs for glycolipid-CD1d complexes.It is anticipated that higher affinity will result in prolonged stimulation of NKT cells and increased cytokinerelease; however, the impact of this affinity on cytokine release profiles is not known and these studies willprovide that information. The number of known organisms producing natural antigens for NKT cells is rathersmall, and bacteria related to those know to stimulate NKT cell directly will be screened for NKT stimulatorybehavior. Structures of antigens will then be determined and confirmed through total synthesis.Relevance to Public Health: Responses of NKT cells influence disease states including infection, tumorrejection, and autoimmune diseases. An understanding of how glycolipids stimulate different responses fromNKT cells will facilitate use of these responses to improve human health. Proposed research will increasethis understanding while augmenting the arsenal of glycolipids that stimulate NKT cells.
Showing the most recent 10 out of 33 publications
