Harnessing NKT Cell Activation by Glycolipids

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Natural Killer T (NKT) cells are potent regulatory T cells that have been shown to be intimately involved in the response to infection and tumor progression. There is also strong evidence that NKT cells may regulate the immune system in such a way as to prevent autoimmunity. Harnessing this activation of NKT cells may provide new therapies for viral and bacterial infections, for cancer and for a range of autoimmune conditions, such as Type I diabetes, multiple sclerosis and lupus. A little more than a decade ago it was revealed that glycolipids, particularly )-galactosylceramides ()- GalCers), could activate NKT cells by serving as ligands to a newly recognized class of antigen presenting proteins, CD1d. For the last five years our lab has designed and synthesized glycosyl ceramides that vary in the ceramide and sugar epitopes in order to probe the role of both regions. In collaboration with immunologists and physical chemists and analytical chemists we propose to continue to investigate the role of glycolipid structure in CD1d mediated immunomodulation with the following goals: 1) )-GalCers with N-anomeric replacements will be synthesized for comparison to the structurally related, but biologically distinct, O-, C- and S-)-GalCers; 2) A set of )-GalCers has been designed and is being synthesized to test the hypothesis that compounds that require antigen processing can be used to induce high levels of Th1 cytokines, which are believed to be responsible for the anti-infective/anti-cancer activities of glycolipids; 3) A recent x-ray report of a ternary complex of )-GalCer/CD1d/NKT T cell receptor will be used to investigate if the saccharide moiety can be used to influence cytokine profiles and/or enhance NKT cell expansion in humans; 4) An MS method for determining anomeric ratios of glycolipids will be developed and used to evaluate the presence of low levels of unwanted anomers.