Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors

The most potent foreign antigens for natural killer T cells (NKT cells) are alpha-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct beta-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 beta-linked agonists beta-galactosylceramide (beta-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 beta-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 beta-linked self ligands to resemble the conformation of foreign alpha-linked ligands, which shows that induced-fit molecular mimicry can underpin the self-reactivity of NKT cell TCRs to beta-linked antigens.