title: Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides.
abstract: The nature of the endogenous ligands for natural killer T (NKT) cells has been debated for more than a decade. Because the mammalian glycosylceramide synthases are invertases, it is believed that in mammals all glycosylceramides are β anomers. However, the possibility that an alternative enzymatic pathway, an unfaithful enzyme, or unique physico-chemical environments could allow the production of small quantities of α anomers should be entertained. Classic biochemical and chemical analysis approaches are not well suited for this challenge as they lack sensitivity. Using a combination of biological assays and new technological approaches, we have unequivocally demonstrated that α glycosylceramides were constitutively produced by mammalian immune cells, loaded onto CD1d and presented to NKT cells both in the thymus and in the periphery. Their amount is controlled tightly by catabolic enzymes, and can be altered in vitro and in vivo to modify NKT cell behavior.
authors.affiliation: The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, CA 92037, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kain
authors.affiliation: The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, CA 92037, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Costanzo
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: The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, CA 92037, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Holt
authors.affiliation: University of Chicago, Committee on Immunology, Chicago, IL 60637, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
authors.affiliation: Brigham Young University, Department of Chemistry, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.affiliation: The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, CA 92037, USA. Electronic address: lteyton@scripps.edu.
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D002518:Ceramides / Q000737:chemistry / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D005964:Glucosyltransferases / Q000235:genetics / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D051146:N-Acylsphingosine Galactosyltransferase / Q000235:genetics / Q000276:immunology; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; D002518:Ceramides; D005964:Glucosyltransferases; D051146:N-Acylsphingosine Galactosyltransferase; C023246:ceramide glucosyltransferase
keywords: Anomers; Ceramide; Contamination; Endogenous ligand; NKT cells; Thymic selection