Highly Selective Cytokine Induction of Nitrated Lipid-Modified α-GalCer Derivatives Demonstrating High Binding Affinity to the Lipid Antigen Presenting Molecule CD1d.

Glycolipid antigens are presented by CD1d on antigen-presenting cells to T cell receptors (TCRs) of natural killer T (NKT) cells, leading to immune responses via cytokine induction. Although various lipid antigens have been found, there are only a limited number of glycolipid antigens having selective cytokine induction. In this study, we identified the glycolipids (α-GalCer nitro-type) that exhibit highly selective induction of Th2 and Th17 type cytokines, with very high binding affinity to CD1d, by introducing nature-inspired nitro-modified fatty acyl groups. The natural nitroalkene moiety of fatty acyl groups in the glycolipids effectively enhances the affinity to CD1d through presumed hydrogen-bonding and NO-π interactions, leading to the distinctive function in cytokine induction and selectivity.