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Anatomy of CD1–lipid antigen complexes

Nature Reviews Immunology volume 5, pages 387–399 (2005)Cite this article

Key Points

  • Human and mouse CD1 proteins are MHC-like molecules that are expressed at the surface of antigen-presenting cells and bind lipids. The recent discovery of many classes of lipid antigens for CD1-restricted T cells implies that the CD1 system surveys cells for changes in their lipid content.

  • Five crystal structures of CD1 proteins bound to lipids have now been solved. These show that the alkyl chains of antigens are inserted into a hydrophobic groove so that their carbohydrate or peptide moieties protrude for contact with T-cell receptors.

  • The general mechanisms of antigen capture by CD1 and MHC proteins differ, as only CD1 uses a deeply buried hydrophobic surface to bind chemically diverse lipid antigens.

  • CD1 grooves are composed of up to four antigen-binding pockets, which are known as the A′, C′, F′ and T′ pockets, and up to two antigen-entry portals that are known as the F′ and C′ portals.

  • Glycolipid–CD1a and lipopeptide–CD1a structures show that the A′ pocket is narrow and has a blunt terminus, which allows it to function as a 'molecular ruler' that binds lipids with a defined alkyl chain length.

  • CD1b proteins can bind antigens with a lipid component that is larger or smaller than the antigen-binding groove. This process probably involves chaperone lipids that bind together with small antigens and the ability of long antigens to protrude through portals so that they lie on the outer surface of the protein.

  • Crystal structures show that CD1a, CD1b and CD1d markedly differ in the size, shape and connectivity of their antigen-binding pockets, which implies that each CD1 protein differs in its specificity for lipid ligands.

Abstract

CD1 proteins bind lipids to form antigen complexes that contact T-cell receptors and activate T cells. Recent crystal structures of CD1 proteins show that their antigen-binding grooves are composed of up to four pockets (A′, C′, F′ and T′) and two antigen portals (C′ and F′). Although certain structural features are conserved among CD1 proteins, the grooves of CD1a, CD1b and CD1d differ in the number, shape and connectivity of their antigen-binding pockets. Here, we outline how the portals and pockets of CD1 antigen-binding grooves influence ligand specificity and facilitate the presentation of a surprisingly diverse set of antigenic lipids, glycolipids, lipopeptides and even small, non-lipidic molecules.

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Figure 1: CD1 pockets and portals.
Figure 2: Antigen-binding surfaces of peptide–MHC and lipid–CD1 complexes.
Figure 3: Functionally important residues that shape CD1 grooves.
Figure 4: Electrostatic topography of the predicted T-cell-receptor-binding surface of CD1 and MHC class I molecules.
Figure 5: Comparison of CD1a binding to a glycolipid and a lipopeptide.
Figure 6: Models of T-cell receptor docking onto lipid–CD1 complexes.
Figure 7: CD1b binding to antigens with varied lipid lengths.

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Acknowledgements

The authors thank C. Roura-Mir, M. Relloso and A. Debono for designs for the CD1 schematics and for discussions and analyses of lipid–CD1 complex structures. This work was supported by grants from the following US organizations: Pew Scholars Program in the Biomedical Sciences, the Cancer Research Institute, The Skaggs Institute for Chemical Biology and the National Institutes of Health (the latter to both D.B.M. and I.A.W.).

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Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Smith Building, Room 514, 1 Jimmy Fund Way, Boston, 02115, Massachusetts, USA

    D. Branch Moody

  2. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Dirk M. Zajonc & Ian A. Wilson

  3. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Ian A. Wilson

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Correspondence to D. Branch Moody.

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DATABASES

Entrez Gene

CD1a

CD1b

CD1c

CD1d

CD1e

OMIM

tuberculosis

Glossary

ALLELIC POLYMORPHISM

Amino-acid sequence alterations in the gene product that are encoded by a given allele, as measured in genetically unrelated members of a population. In contrast to the high rates of allelic polymorphism that produce many MHC molecules with diverse antigen-binding specificities, CD1 proteins show low levels of polymorphism, which are comparable with those of other somatic proteins.

β-SHEET PLATFORM

Several β-strands interact with each other to from a hydrogen-bonded β-sheet that is often referred to as a 'platform' if other structural elements (such as helices) sit atop it, as occurs in CD1 proteins and MHC class I and class II molecules.

VAN DER WAALS INTERACTIONS

Also known as London forces (after Fritz London), these weak intermolecular forces arise from the attractive force between transient dipoles in otherwise non-polar molecules.

pKa

The inverse log of the acid dissociation constant, which can be used to predict the charge state of an amino-acid side chain as a function of pH.

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Moody, D., Zajonc, D. & Wilson, I. Anatomy of CD1–lipid antigen complexes. Nat Rev Immunol 5, 387–399 (2005). https://doi.org/10.1038/nri1605

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