Sandrine Aspeslagh, Yali Li, Esther Dawen Yu, Nora Pauwels, Matthias Trappeniers, Enrico Girardi, Tine Decruy, Katrien Van Beneden, Koen Venken, Michael Drennan, Luc Leybaert, Jing Wang, Richard W Franck, Serge Van Calenbergh, Dirk M Zajonc, Dirk Elewaut
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 α-galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior 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.
Aspeslagh, S, Li, Y, Yu, ED, Pauwels, N, Trappeniers, M, Girardi, E, Decruy, T, Van Beneden, K, Venken, K, Drennan, M, Leybaert, L, Wang, J, Franck, RW, Van Calenbergh, S, Zajonc, DM & Elewaut, D 2011, 'Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis', EMBO Journal, vol. 30, no. 11, pp. 2294-2305. https://doi.org/10.1038/emboj.2011.145
Aspeslagh, S., Li, Y., Yu, E. D., Pauwels, N., Trappeniers, M., Girardi, E., Decruy, T., Van Beneden, K., Venken, K., Drennan, M., Leybaert, L., Wang, J., Franck, R. W., Van Calenbergh, S., Zajonc, D. M., & Elewaut, D. (2011). Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis. EMBO Journal, 30(11), 2294-2305. https://doi.org/10.1038/emboj.2011.145
@article{5ea9163880d842b3a7f0e559b339f46c,
title = "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 α-galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior 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.",
keywords = "Animals, Antigens, CD1d/metabolism, Galactosylceramides/metabolism, Mice, Natural Killer T-Cells/immunology, Neoplasm Metastasis/immunology, Neoplasms/immunology, Protein Binding",
author = "Sandrine Aspeslagh and Yali Li and Yu, {Esther Dawen} and Nora Pauwels and Matthias Trappeniers and Enrico Girardi and Tine Decruy and {Van Beneden}, Katrien and Koen Venken and Michael Drennan and Luc Leybaert and Jing Wang and Franck, {Richard W} and {Van Calenbergh}, Serge and Zajonc, {Dirk M} and Dirk Elewaut",
year = "2011",
month = jun,
day = "1",
doi = "10.1038/emboj.2011.145",
language = "English",
volume = "30",
pages = "2294--2305",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "11",
}