title: The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian α-linked glycosylceramides.
abstract: Glycosylceramides in mammalian species are thought to be present in the form of β-anomers. This conclusion was reinforced by the identification of only one glucosylceramide and one galactosylceramide synthase, both β-transferases, in mammalian genomes. Thus, the possibility that small amounts of α-anomers could be produced by an alternative enzymatic pathway, by an unfaithful enzyme, or spontaneously in unusual cellular compartments has not been examined in detail. We approached the question by taking advantage of the exquisite specificity of T and B lymphocytes and combined it with the specificity of catabolic enzymes of the sphingolipid pathway. Here, we demonstrate that mammalian immune cells produce constitutively very small quantities of α-glycosylceramides, which are the major endogenous ligands of natural killer T cells. Catabolic enzymes of the ceramide and glycolipid pathway tightly control the amount of these α-glycosylceramides. The exploitation of this pathway to manipulate the immune response will create new therapeutic opportunities.
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kain
authors.affiliation: Department of Molecular Biology, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Webb
authors.affiliation: Department of Chemistry, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Anderson
authors.affiliation: Department of Chemistry, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Shenglou
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Holt
authors.forename: Anne
authors.initials: A
authors.lastname: Costanzo
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Constanzo
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Self
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Anais
authors.initials: A
authors.lastname: Teyton
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Everett
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
authors.affiliation: Department of Chemistry, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.affiliation: Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: lteyton@scripps.edu.
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
mesh_terms: D000818:Animals; D055610:Antigens, CD1d; D001402:B-Lymphocytes / Q000201:enzymology*; D002460:Cell Line; D005963:Glucosylceramides / Q000096:biosynthesis* / Q000276:immunology; D006017:Glycolipids / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000201:enzymology*
chemical_list: D055610:Antigens, CD1d; D005963:Glucosylceramides; D006017:Glycolipids