CD1d-lipid antigen recognition by the γδ TCR

How γδ TCRs bind antigen presented by antigen-presenting molecules remains unclear. Godfrey and colleagues describe a population of human γδ T cells that interacts with CD1d and provide a molecular basis for how a γδ TCR binds CD1d–α-GalCer. The T cell repertoire comprises αβ and γδ T cell lineages. Although it is established how αβ T cell antigen receptors (TCRs) interact with antigen presented by antigen-presenting molecules, this is unknown for γδ TCRs. We describe a population of human V δ 1 + γδ T cells that exhibit autoreactivity to CD1d and provide a molecular basis for how a γδ TCR binds CD1d–α-galactosylceramide (α-GalCer). The γδ TCR docked orthogonally, over the A′ pocket of CD1d, in which the V δ 1-chain, and in particular the germ line–encoded CDR1δ loop, dominated interactions with CD1d. The TCR γ- chain sat peripherally to the interface, with the CDR3γ loop representing the principal determinant for α-GalCer specificity. Accordingly, we provide insight into how a γδ TCR binds specifically to a lipid-loaded antigen-presenting molecule.