Crystal Structure of Vδ1 T Cell Receptor in Complex with CD1d-Sulfatide Shows MHC-like Recognition of a Self-Lipid by Human γδ T Cells

The nature of the antigens recognized by gamma delta T cells and their potential recognition of major histocompatibility complex (MHC)-like molecules has remained unclear. Members of the CD1 family of lipid-presenting molecules are suggested ligands for V delta 1 TCR-expressing gamma delta T cells, the major gamma delta lymphocyte population in epithelial tissues. We crystallized a V delta 1 TCR in complex with CD1d and the self-lipid sulfatide, revealing the unusual recognition of CD1d by germline V delta 1 residues spanning all complementarity-determining region (CDR) loops, as well as sulfatide recognition separately encoded by non-germline CDR3d residues. Binding and functional analysis showed that CD1d presenting self-lipids, including sulfatide, was widely recognized by gut V delta 1+ gamma delta T cells. These findings provide structural demonstration of MHC-like recognition of a self-lipid by gamma delta T cells and reveal the prevalence of lipid recognition by innate-like T cell populations.