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.
authors.affiliation: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, Ghent, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Aspeslagh
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.forename: Esther Dawen
authors.initials: ED
authors.lastname: Yu
authors.forename: Nora
authors.initials: N
authors.lastname: Pauwels
authors.forename: Matthias
authors.initials: M
authors.lastname: Trappeniers
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.forename: Tine
authors.initials: T
authors.lastname: Decruy
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Beneden
authors.forename: Koen
authors.initials: K
authors.lastname: Venken
authors.forename: Michael
authors.initials: M
authors.lastname: Drennan
authors.forename: Luc
authors.initials: L
authors.lastname: Leybaert
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Richard W
authors.initials: RW
authors.lastname: Franck
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism*; D005699:Galactosylceramides / Q000378:metabolism*; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*; D009362:Neoplasm Metastasis / Q000276:immunology / Q000517:prevention & control*; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control*; D011485:Protein Binding
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D005699:Galactosylceramides; C493154:alpha-galactosylceramide