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¹ Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
² Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037
³ Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037
⁴ Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

CORRESPONDENCE Ian A. Wilson: wilson{at}scripps.edu OR Vipin Kumar: vkumar{at}tpims.org

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 Å 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 ß linkage, compared with the more intimate binding of the -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.

Abbreviations used: -GalCer, -galactosyl ceramide; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; Endo H, Endoglycosidase H; iGB3, isoglobotrihexosyl ceramide; MS, multiple sclerosis; NKT, natural killer T; PC, phosphatidyl choline; SF9, Spodoptera frugiperda.

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