title: Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.
abstract: Sulfatide derived from the myelin stimulates a distinct population of CD1d-restricted natural killer T (NKT) cells. Cis-tetracosenoyl sulfatide is one of the immunodominant species in myelin as identified by proliferation, cytokine secretion, and CD1d tetramer staining. The crystal structure of mouse CD1d in complex with cis-tetracosenoyl sulfatide at 1.9 A resolution reveals that the longer cis-tetracosenoyl fatty acid chain fully occupies the A' pocket of the CD1d binding groove, whereas the sphingosine chain fills up the F' pocket. A precise hydrogen bond network in the center of the binding groove orients and positions the ceramide backbone for insertion of the lipid tails in their respective pockets. The 3'-sulfated galactose headgroup is highly exposed for presentation to the T cell receptor and projects up and away from the binding pocket due to its beta linkage, compared with the more intimate binding of the alpha-glactosyl ceramide headgroup to CD1d. These structure and binding data on sulfatide presentation by CD1d have important implications for the design of therapeutics that target T cells reactive for myelin glycolipids in autoimmune diseases of the central nervous system.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.forename: Igor
authors.initials: I
authors.lastname: Maricic
authors.forename: Douglass
authors.initials: D
authors.lastname: Wu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Halder
authors.forename: Keshab
authors.initials: K
authors.lastname: Roy
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Vipin
authors.initials: V
authors.lastname: Kumar
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018949:Antigens, CD1 / Q000737:chemistry* / Q000276:immunology; D055610:Antigens, CD1d; D015551:Autoimmunity / Q000276:immunology; D002417:Cattle; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000737:chemistry* / Q000276:immunology; D017434:Protein Structure, Tertiary; D013433:Sulfoglycosphingolipids / Q000737:chemistry* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D016207:Cytokines; D005699:Galactosylceramides; D013433:Sulfoglycosphingolipids