Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.
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.
Zajonc
Dirk M
DM
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Maricic
Igor
I
Wu
Douglass
D
Halder
Ramesh
R
Roy
Keshab
K
Wong
Chi-Huey
CH
Kumar
Vipin
V
Wilson
Ian A
IA
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
D018949:Antigens, CD1; D055610:Antigens, CD1d; D016207:Cytokines; D005699:Galactosylceramides; D013433:Sulfoglycosphingolipids