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Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor

Nature Immunology volume 6, pages 810–818 (2005)Cite this article

Abstract

Natural killer T cells express a conserved, semi-invariant αβ T cell receptor that has specificity for self glycosphingolipids and microbial cell wall α-glycuronosylceramide antigens presented by CD1d molecules. Here we report the crystal structure of CD1d in complex with a short-chain synthetic variant of α-galactosylceramide at a resolution of 2.2 Å. This structure elucidates the basis for the high specificity of these microbial ligands and explains the restriction of the α-linkage as a unique pathogen-specific pattern-recognition motif. Comparison of the binding of altered lipid ligands to CD1d and T cell receptors suggested that the differential T helper type 1–like and T helper type 2–like properties of natural killer T cells may originate largely from differences in their 'loading' in different cell types and hence in their tissue distribution in vivo.

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Figure 1: PBS-25 is an agonist of NKT cells.
Figure 2: Kinetics of the binding of PBS-25 to CD1d.
Figure 3: Overview of the mouse CD1d structure with bound PBS-25 glycolipid.
Figure 4: Conformation of the short α-GalCer in the mouse CD1d binding groove.
Figure 5: 'Stereo' view of the specific hydrogen bond network between mouse CD1d and an α-GalCer ligand.
Figure 6: CD1d antigen-binding grooves with crystallized or modeled ligands.
Figure 7: Pharmacological distribution of α-GalCer and PBS-25.

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Acknowledgements

We thank the staff of the Advanced Light Source BL 8.2.2 for support with data collection; P. Wright and L. Tennant for help with the circular dichroism experiments; and R. Stanfield for help with data analysis. Supported by the National Institutes of Health (AI053725 to L.T., A.B. and P.B.S.; GM62116 and CA58896 to I.A.W.), Skaggs Institute for Chemical Biology (D.M.Z. and I.A.W.) and Cancer Research Institute (J.M.).

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Authors and Affiliations

  1. Department of Molecular Biology and The Scripps Research Institute, La Jolla, 92037, California, USA

    Dirk M Zajonc & Ian A Wilson

  2. Department of Immunology and The Scripps Research Institute, La Jolla, 92037, California, USA

    Carlos Cantu III & Luc Teyton

  3. Committee on Immunology, University of Chicago, Chicago, 60637, Illinois, USA

    Jochen Mattner, Dapeng Zhou & Albert Bendelac

  4. Brigham Young University, C100 Benson Science Building, Provo, 84602-5700, Utah, USA

    Paul B Savage

  5. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Ian A Wilson

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Zajonc, D., Cantu, C., Mattner, J. et al. Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor. Nat Immunol 6, 810–818 (2005). https://doi.org/10.1038/ni1224

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