title: Enhanced TCR footprint by a novel glycolipid increases NKT-dependent tumor protection.
abstract: NKT cells, a unique type of regulatory T cells, respond to structurally diverse glycolipids presented by CD1d. Although it was previously thought that recognition of glycolipids such as α-galactosylceramide (α-GalCer) by the NKT cell TCR (NKTCR) obeys a key-lock principle, it is now clear this interaction is much more flexible. In this article, we report the structure-function analysis of a series of novel 6''-OH analogs of α-GalCer with more potent antitumor characteristics. Surprisingly, one of the novel carbamate analogs, α-GalCer-6''-(pyridin-4-yl)carbamate, formed novel interactions with the NKTCR. This interaction was associated with an extremely high level of Th1 polarization and superior antitumor responses. These data highlight the in vivo relevance of adding aromatic moieties to the 6''-OH position of the sugar and additionally show that judiciously chosen linkers are a promising strategy to generate strong Th1-polarizing glycolipids through increased binding either to CD1d or to NKTCR.
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors: Sandrine
authors: S
authors: Aspeslagh
authors: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Marek
authors: M
authors: Nemčovič
authors: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors: Nora
authors: N
authors: Pauwels
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors: Koen
authors: K
authors: Venken
authors: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Jing
authors: J
authors: Wang
authors: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors: Serge Van
authors: SV
authors: Calenbergh
authors: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Dirk M
authors: DM
authors: Zajonc
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors: Dirk
authors: D
authors: Elewaut
mesh_terms: D000818:Animals; D005699:Galactosylceramides / Q000276:immunology*; D006017:Glycolipids / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D005699:Galactosylceramides; D006017:Glycolipids; D011948:Receptors, Antigen, T-Cell; C493154:alpha-galactosylceramide
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