Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis

Abstract

Invariant natural killer T (iNKT) cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. Here, we report the structure and function of a novel class of aromatic alpha-galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior tumour protection in vivo. The strength of the Thl 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, alpha-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

Bacterial CD1d–Restricted Glycolipids Induce IL-10 Production by Human Regulatory T Cells upon Cross-Talk with Invariant NKT Cells

“…In our proliferation assay, it was apparent that C9:0 and OCH responses were relatively weak compared with a-GalCer, and they were easily suppressed by Tregs. In contrast, NU-a-GalCer, a 69-OH group modified analog recently described by our group (21), induced a robust iNKT activation; however, this response was only modestly inhibited with the addition of high Treg numbers, as was also observed for a-GalCer. Reducing the proportion of a-GalCer-loaded APCs opened a window for Tregs to also suppress these stronger responses more efficiently.…”

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

“…3B). Crystal structure analysis demonstrated that the naphthyl urea group folds over and makes additional contacts with the surface of the CD1d molecule when the TCR is engaged (35). Conversely, the GSL OCH (Fig.…”

Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation

“…However, unlike NU-␣GC where the naphthyl is linked via a urea group, NC-␣GC has a carbamate linker, which provides more flexibility to the naphthyl moiety (18). The rationale of introducing this flexible linker was to assess whether the rigidity of the urea linker or the aromatic nature and size of the naphthyl group cause the reported structural change in the AЈ roof of CD1d (36). EF77 is a plakoside A-like glycolipid, a GSL isolated from the marine sponge, Plakortis simplex (37), and is related to the previously crystallized SMC124 lipid (16).…”

“…It is perhaps this alteration from an O-glycoside bond to a carbon linkage that slightly alters the binding of the glycolipid within CD1d. A rotation of the 3Ј-OH of the sphingoid base followed by concomitant loss of a hydrogen bond with Asp-80 of CD1d has been observed in two separate crystal structures (36,49). Nonetheless, lipids of this nature do not appear to exhibit the same therapeutic potential than the other lipids in our assays.…”