Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity

Area of Science:

• Immunology
• Structural Biology
• Neuroscience

Background:

• Myelin contains sulfatides that stimulate CD1d-restricted natural killer T (NKT) cells.
• Cis-tetracosenoyl sulfatide is a key immunodominant myelin species.
• NKT cells play a role in autoimmune diseases of the central nervous system.

Purpose of the Study:

• To determine the crystal structure of mouse CD1d in complex with cis-tetracosenoyl sulfatide.
• To elucidate the binding interactions between sulfatide and the CD1d molecule.
• To understand the presentation of myelin glycolipids to NKT cells.

Main Methods:

• X-ray crystallography at 1.9 Å resolution.
• Analysis of protein-ligand interactions.
• CD1d tetramer staining and cytokine secretion assays.

Main Results:

• The crystal structure reveals how the cis-tetracosenoyl fatty acid chain and sphingosine chain occupy specific pockets (A' and F') within the CD1d binding groove.
• A hydrogen bond network precisely orients the ceramide backbone.
• The sulfated galactose headgroup is exposed for T cell receptor interaction, projecting away from the binding pocket due to its beta linkage.

Conclusions:

• The detailed structure and binding mechanism of sulfatide presentation by CD1d are revealed.
• These findings provide a structural basis for understanding NKT cell activation by myelin glycolipids.
• The data have significant implications for designing therapeutics targeting myelin-reactive T cells in central nervous system autoimmune diseases.