The CD1 family is a large cluster of non-polymorphic, major histocompatibility complex (MHC) class-I-like molecules that bind distinct lipid-based antigens that are recognized by T cells. The most studied group of T cells that interact with lipid antigens are natural killer T (NKT) cells, which characteristically express a semi-invariant T-cell receptor (NKT TCR) that specifically recognizes the CD1 family member, CD1d. NKT-cell-mediated recognition of the CD1d–antigen complex has been implicated in microbial immunity, tumour immunity, autoimmunity and allergy. Here we describe the structure of a human NKT TCR in complex with CD1d bound to the potent NKT-cell agonist α-galactosylceramide, the archetypal CD1d-restricted glycolipid. In contrast to T-cell receptor–peptide-antigen–MHC complexes, the NKT TCR docked parallel to, and at the extreme end of the CD1d-binding cleft, which enables a lock-and-key type interaction with the lipid antigen. The structure provides a basis for the interaction between the highly conserved NKT TCR α-chain and the CD1d–antigen complex that is typified in innate immunity, and also indicates how variability of the NKT TCR β-chain can impact on recognition of other CD1d–antigen complexes. These findings provide direct insight into how a T-cell receptor recognizes a lipid-antigen-presenting molecule of the immune system.
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We thank the staff at the IMCA beamline at the Advanced Photon Source for assistance with data collection. The Australian Research Council (ARC), the National Health and Medical Research Council of Australia (NHMRC), the Cancer Council of Victoria and a Monash Early Career Research grant (N.A.B.) supported this research. D.G.P. and D.I.G. receive support from an RO1 grant from the National Institutes of Health and the Association of International Cancer Research. G.S.B. acknowledges support in the form of a Personal Research Chair from J. Bardrick, as a former Lister Institute-Jenner Research Fellow, the Medical Research Council (UK) and the Wellcome Trust; N.A.B. is supported by an NHMRC Peter Doherty Fellowship, D.I.G. by an NHMRC Principal Research Fellowship, and M.C.J.W. by an NHMRC Senior Research Fellowship. J.R. is supported by an ARC Federation Fellowship.
Author Contributions N.A.B. performed experimental work, analysis and prepared the manuscript; K.S.W., L.K.N., M.C.J.W., D.P., M.B. performed experimental work; G.S.B. provided essential reagents; D.I.G. devised the project, analysed data and wrote the manuscript; and J.M. and J.R. are joint senior and corresponding authors—they co-led the investigation, devised the project, analysed the data and wrote the manuscript.
The X-ray crystallographic coordinates and structure factor files have been deposited in the Protein Data Bank with accession number 2PO6.
The X-ray crystallographic coordinates and structure factor files have been deposited in the Protein Data Bank with accession number 2PO6. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains Supplementary Figures S1-S5 with Legends and Supplementary Tables S1-S2. (PDF 1336 kb)
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