Glycolipids that Elicit IFN-γ-Biased Responses from Natural Killer T Cells

Natural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, alpha-galactosyl ceramide (alpha GalCer), is a potential anticancer agent whose activity depends upon IFN-gamma secretion. We report two analogs of aGalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-gamma that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-gamma-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility.