The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding these disparate antigens, the NKT cell TCRs docked onto CD1d similarly, achieving this by flattening the conformation of the β-linked ligands regardless of the size of the glycosyl head group. Unexpectedly, the antigenicity of iGb3 was attributable to its terminal sugar group making compensatory interactions with CD1d. Thus, the NKT cell TCR molds the β-linked self ligands to resemble the conformation of foreign α-linked ligands, which shows that induced-fit molecular mimicry can underpin the self-reactivity of NKT cell TCRs to β-linked antigens.
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We thank F. Carbone for critically reading the manuscript; K. Wun, R. Koh and M. Sandoval for assistance; and J. Vivian and the staff at the MX2 beamline of the Australian synchrotron for assistance with data collection. Supported by the Cancer Council of Victoria, the National Health and Medical Research Council of Australia, the Australian Research Council, The Royal Society (G.S.B.), The Wellcome Trust (084923/B/08/Z to G.S.B.), the Medical Research Council (G1001750 to G.S.B.) and the US National Institutes of Health (AI45889 to S.A.P., and AI076463 and AI078246 to L.G.).
S.A.P. has received payments as a consultant for Vaccinex for work related to the development of therapeutics based on CD1d-presented glycolipids.
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Pellicci, D., Clarke, A., Patel, O. et al. Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors. Nat Immunol 12, 827–833 (2011). https://doi.org/10.1038/ni.2076
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