A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen–recognition properties

Abstract

Type I natural killer T cells (NKT cells) are characterized by an invariant variable region 14–joining region 18 (Vα14-Jα18) T cell antigen receptor (TCR) α-chain and recognition of the glycolipid α-galactosylceramide (α-GalCer) restricted to the antigen-presenting molecule CD1d. Here we describe a population of α-GalCer-reactive NKT cells that expressed a canonical Vα10-Jα50 TCR α-chain, which showed a preference for α-glucosylceramide (α-GlcCer) and bacterial α-glucuronic acid–containing glycolipid antigens. Structurally, despite very limited TCRα sequence identity, the Vα10 TCR–CD1d–α-GlcCer complex had a docking mode similar to that of type I TCR–CD1d–α-GalCer complexes, although differences at the antigen-binding interface accounted for the altered antigen specificity. Our findings provide new insight into the structural basis and evolution of glycolipid antigen recognition and have notable implications for the scope and immunological role of glycolipid-specific T cell responses.

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Figure 1: Identification of Jα18−/− T cells reactive to CD1d–α-GalCer.
Figure 2: Jα18−/− CD1d–α-GalCer+ NKT cells express a semi-invariant Vα10-Jα50–Vβ8+ TCR.
Figure 3: Vα10 NKT cells have a unique hierarchy of antigen recognition.
Figure 4: Vα10 NKT cells have a higher affinity for α-GlcCer and are present in wild-type mice.
Figure 5: Structural comparison of Vα10 NKT cell TCR–CD1d–α-GlcCer and type I NKT cell TCR–CD1d–α-GalCer.
Figure 6: CD1d-mediated interactions with Vα10–Vβ8.1 NKT cell TCR.
Figure 7: Lipid antigen specificity.

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Acknowledgements

We thank M. Taniguchi (Chiba University Graduate School of Medicine) for Jα18−/− mice; M. Kronenberg (La Jolla Institute for Allergy and Immunology) for the baculovirus-based CD1d expression system; P. Savage (Brigham Young University) for α-GalCer (C24:1 PBS-44 analog); the Australian Synchrotron staff at the MX1 and MX2 beamlines of the Australian synchrotron for assistance with data collection; S. Mattarollo, S. Doak, S. Berzins and A. Denton for discussions and assistance with some experiments; K. Field, N. Sanders and M. Reitsma for assistance with flow cytometry; and M. Stirling and the staff of the Peter MacCallum Cancer Centre Animal House and D. Maksel from the Protein Crystallography Unit at Monash University for technical assistance. Supported by the Cancer Council of Victoria, the National Health and Medical Research Council of Australia (A.P.U., L.C.S., M.J.S. and D.I.G.), the Australian Research Council (D.I.G., O.P. and J.R.), the Cancer Research Institute (G.C.) and the US National Institutes of Health (AI45889 to S.A.P.).

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A.P.U. identified and carried out cellular and molecular characterization of Vα10 NKT cells and produced protein complexes for crystallographic studies; O.P. solved the crystal structures and did structural analysis; G.C. and K.K. carried out studies of glycolipid specificity and function; L.C.S. did surface plasmon resonance studies; D.G.P., E.B.D., L.K.-N., J.P.V., S.J.T., G.S.B., B.C., A.G.B., S.J.W., P.I., S.A.P., J.M., M.J.S., J.R. and D.I.G. provided intellectual input and key reagents and assisted with experimental design and interpretation and writing of the manuscript; and M.J.S., J.R. and D.I.G. led the investigation together and devised the project and contributed equally to this work.

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Correspondence to Jamie Rossjohn or Dale I Godfrey.

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S.A.P. has received payment as a consultant for Vaccinex for work related to the development of therapeutics based on glycolipids pretreated with CD1d.

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Uldrich, A., Patel, O., Cameron, G. et al. A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen–recognition properties. Nat Immunol 12, 616–623 (2011). https://doi.org/10.1038/ni.2051

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