title: Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation.
abstract: The ability of different glycosphingolipids (GSLs) to activate type I natural killer T cells (NKT cells) has been known for 2 decades. The possible therapeutic use of these GSLs has been studied in many ways; however, studies are needed in which the efficacy of promising GSLs is compared under identical conditions. Here, we compare five unique GSLs structurally derived from α-galactosylceramide. We employed biophysical and biological assays, as well as x-ray crystallography to study the impact of the chemical modifications of the antigen on type I NKT cell activation. Although all glycolipids are bound by the T cell receptor of type I NKT cells in real time binding assays with high affinity, only a few activate type I NKT cells in in vivo or in vitro experiments. The differences in biological responses are likely a result of different pharmacokinetic properties of each lipid, which carry modifications at different parts of the molecule. Our results indicate a need to perform a variety of assays to ascertain the therapeutic potential of type I NKT cell GSL activators.
authors.affiliation: From the Division of Cell Biology and Division of Developmental Immunology,La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, the Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037.
authors.forename: Alysia
authors.initials: A
authors.lastname: Birkholz
authors.affiliation: From the Division of Cell Biology and.
authors.forename: Marek
authors.initials: M
authors.lastname: Nemčovič
authors.affiliation: From the Division of Cell Biology and.
authors.forename: Esther Dawen
authors.initials: ED
authors.lastname: Yu
authors.affiliation: From the Division of Cell Biology and.
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.affiliation: From the Division of Cell Biology and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Developmental Immunology,La Jolla Institute for Allergy and Immunology, La Jolla, California 92037.
authors.forename: Archana
authors.initials: A
authors.lastname: Khurana
authors.affiliation: the Laboratory for Medicinal Chemistry, Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium.
authors.forename: Nora
authors.initials: N
authors.lastname: Pauwels
authors.affiliation: the Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Farber
authors.affiliation: the Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, and.
authors.forename: Sampada
authors.initials: S
authors.lastname: Chitale
authors.affiliation: the Department of Chemistry, Hunter College of City University of New York, New York, New York 10021.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Franck
authors.affiliation: the Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016.
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: the Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, and.
authors.forename: Amy
authors.initials: A
authors.lastname: Howell
authors.affiliation: the Laboratory for Medicinal Chemistry, Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium.
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.affiliation: Division of Developmental Immunology,La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, the Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.affiliation: From the Division of Cell Biology and the Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium dzajonc@lji.org.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D055610:Antigens, CD1d / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D005699:Galactosylceramides / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000145:classification / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; C584692:CD1d antigen, mouse; D005699:Galactosylceramides; D006028:Glycosphingolipids; D046912:Multiprotein Complexes; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493154:alpha-galactosylceramide
keywords: T cell receptor (TCR); cytokine induction; glycolipid structure; immunology; protein crystallization; surface plasmon resonance (SPR)