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Germline-encoded recognition of diverse glycolipids by natural killer T cells

Nature Immunology volume 8, pages 1105–1113 (2007)Cite this article

Abstract

Natural killer T cells expressing 'invariant' T cell receptor α-chains (TCRα chains) containing variable (V) and joining (J) region Vα14-Jα18 (Vα14i) rearrangements recognize both endogenous and microbial glycolipids in the context of CD1d. How cells expressing an invariant TCRα chain and a restricted set of TCRβ chains recognize structurally diverse antigens is not clear. Here we show that a Vα14i TCR recognized many α-linked glycolipids by means of a 'hot-spot' of germline-encoded amino acids in complementarity-determining regions 3α, 1α and 2β. This hot-spot did not shift during the recognition of structurally distinct antigens, suggesting that the Vα14i TCR functions as a pattern-recognition receptor, conferring on natural killer T cells the ability to sense and respond in an innate way to pathogens displaying antigenic α-linked glycolipids.

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Figure 1: A single Vα14i TCR recognizes five distinct glycolipids.
Figure 2: Substitution of the Vα14i TCR similarly affects the recognition of CD1d loaded with α-GalCer, PBS57 or OCH9.
Figure 3: Substitution of the Vα14i TCR similarly affects the recognition of CD1d loaded with GSL-1′ or iGb3.
Figure 4: Substitution of the Vα14i-DOβ TCR similarly affects the recognition of mouse and human CD1d.
Figure 5: CDR3β diversity does not mediate 'preferential' recognition of different glycolipid antigens.
Figure 6: A germline-encoded surface is required for recognition of CD1d-glycolipid complexes.

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Acknowledgements

We thank J. Cambier, P. Henson, E. Huseby and R. Torres for discussions and comments on the manuscript; J. Loomis for assistance with flow cytometry; and the National Institutes of Health core facility for CD1d tetramers. The GSL-1′ compound was provided by M. Kronenberg and Y. Kinjo (La Jolla Institute for Allergy and Immunology); the mouse stem cell virus–based retroviral plasmids with a human nerve growth factor reporter were provided by S. Reiner (University of Pennsylvania); and B78hi cells were provided by H. Levitski (Johns Hopkins University). Supported by the National Institutes of Health (AI057485 to L.G., AI18785 to P.M. and AI17134 to J.K.), the Howard Hughes Medical Institute (P.M. and J.K.), the Australian Research Council Federation (J.R.), the National Health and Medical Research Council (J.M. and J.R.; Peter Doherty Fellowship to N.A.B.), the Cancer Council of Victoria (J.M. and J.R.) and the American Cancer Society (J.L.M.).

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Author notes

  1. James P Scott-Browne and Jennifer L Matsuda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, 80206, Colorado, USA

    James P Scott-Browne, Jennifer L Matsuda, Thierry Mallevaey, Janice White, John Kappler, Philippa Marrack & Laurent Gapin

  2. Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, School of Biomedical Sciences, Monash University, Clayton, 3800, Victoria, Australia

    Natalie A Borg & Jamie Rossjohn

  3. Department of Microbiology and Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    James McCluskey

  4. Howard Hughes Medical Institute and University of Colorado Health Sciences Center, Denver, 80220, Colorado, USA

    John Kappler & Philippa Marrack

  5. Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Ist 80220, USA.,

    John Kappler

  6. Department of Medicine, University of Colorado Health Sciences Center, Denver, 80220, Colorado, USA

    John Kappler & Philippa Marrack

  7. Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, 80220, Colorado, USA

    Philippa Marrack

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Contributions

J.P.S.-B., J.L.M., T.M. and L.G. did the experimental work and analysis and prepared the manuscript; J.W., N.A.B., J.M. and J.R. provided reagents and crystallographic data; and J.P.S.-B., J.K., P.M. and L.G. devised the project, analyzed the data and wrote the manuscript.

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Correspondence to Laurent Gapin.

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Scott-Browne, J., Matsuda, J., Mallevaey, T. et al. Germline-encoded recognition of diverse glycolipids by natural killer T cells. Nat Immunol 8, 1105–1113 (2007). https://doi.org/10.1038/ni1510

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