Mechanisms for Glycolipid Antigen-Driven Cytokine Polarization by Vα14i NKT Cells

Abstract

Certain glycolipid Ags for Vα14i NKT cells can direct the overall cytokine balance of the immune response. Th2-biasing OCH has a lower TCR avidity than the most potent agonist known, α-galactosylceramide. Although the CD1d-exposed portions of OCH and α-galactosylceramide are identical, structural analysis indicates that there are subtle CD1d conformational differences due to differences in the buried lipid portion of these two Ags, likely accounting for the difference in antigenic potency. Th1-biasing C-glycoside/CD1d has even weaker TCR interactions than OCH/CD1d. Despite this, C-glycoside caused a greater downstream activation of NK cells to produce IFN-γ, accounting for its promotion of Th1 responses. We found that this difference correlated with the finding that C-glycoside/CD1d complexes survive much longer in vivo. Therefore, we suggest that the pharmacokinetic properties of glycolipids are a major determinant of cytokine skewing, suggesting a pathway for designing therapeutic glycolipids for modulating invariant NKT cell responses.

Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy

“…However, α-C-GalCer was more resistant to O-glycosidase degradation in vivo. Thus, CD1d-α-C-GalCer displayed longer half-life in vivo and stimulated iNKTcells longer (26). This may explain why the secretion of IFN-γ peaked at 24 h after α-CGalCer injection while it peaked around 12 to approximately 18 h after α-GalCer stimulation (32).…”

“…Moreover, the rate of dissociation of CD1d-glycolipid complex from iNKT TCR could affect the duration of its interaction with TCR. To determine the half-life of ternary interaction, the decay of the percentage staining for dimer on iNKT cells was measured so as to assess the binding stability of the interaction between the dimer complexes and iNKT TCRs, as described previously (26). The mCD1d-glycolipid complexes were incubated with Vβ8.2 þ Vα14iNKT hybridoma cells, the dissociated complexes were washed away at the indicated time points, and the remaining bound complexes were analyzed by FACS (Fig.…”

Fine tuning by human CD1e of lipid-specific immune responses

“…CD1e might directly influence the number of CD1d-antigen complexes available over time, which has been shown to affect the type of cytokines released (12)(13)(14). To test this possibility, antigen-pulse experiments were performed to compare the time required for the generation of CD1d-antigen stimulatory complexes.…”

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

“…Among the factors that might contribute to prolonged antigenic stimulation, increased TCR affinity for the GSL-CD1d complex is not a good predictor of the type of immune response that will result (28,29). Multiple studies have demonstrated that it is difficult to obtain a GSL with a higher affinity than ␣GalCer for the iNKT cell TCR by altering the sugar head group or by modifying the ceramide lipid in either the sphingoid base or the carboxylic acid.…”