Functional and structural characterization of potent Th1 biasing 6′-derivatised α-GalCer iNKT cell agonists, and their superior role in tumor protection. (156.4)

Abstract

Abstract Invariant natural killer T cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. In this study, we report the first crystal structures of a novel class of strong Th1 biasing structural analogues of α-galactosylceramide by addition of aromatic structures on the 6-OH position of galactose. They are characterized by marked Th1 polarized cytokine patterns that are highly conserved between mice and men, and marked tumour protection in vivo. The strength of the Th1 response correlates well with enhanced lipid binding to CD1d as a result of an induced fit mechanism that binds the aromatic substitution as a third anchor, in addition to the two lipid chains. This induced fit is in contrast to another Th1 biasing glycolipid, α-C-GalCer, whose CD1d binding follows a conventional key-lock principle. These findings highlight the previously unexploited flexibility of CD1d in accommodating galactose-modified glycolipids and broaden the range of glycolipids that can stimulate iNKT cells. We speculate that glycolipids can be designed that induce a similar fit, thereby leading to superior and more sustained iNKT cell responses in vivo.