CD1d-lipid antigen recognition by the γδ TCR

The T cell repertoire comprises alpha beta and gamma delta T cell lineages. Although it is established how alpha beta T cell antigen receptors (TCRs) interact with antigen presented by antigen-presenting molecules, this is unknown for gamma delta TCRs. We describe a population of human V(delta)1(+) gamma delta T cells that exhibit autoreactivity to CD1d and provide a molecular basis for how a gamma delta TCR binds CD1d-alpha-galactosylceramide (alpha-GalCer). The gamma delta TCR docked orthogonally, over the A' pocket of CD1d, in which the V(delta)1-chain, and in particular the germ line-encoded CDR1 delta loop, dominated interactions with CD1d. The TCR gamma-chain sat peripherally to the interface, with the CDR3 gamma loop representing the principal determinant for alpha-GalCer specificity. Accordingly, we provide insight into how a gamma delta TCR binds specifically to a lipid-loaded antigen-presenting molecule.