The γδ T cell receptor combines innate with adaptive immunity by utilizing spatially distinct regions for agonist-selection and antigen responsiveness

T cell receptor (TCR) γδ-expressing T lymphocytes compose evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded γδ T cells with unique specificities typify adaptive immunity. Conversely, large TCRγδ + intraepithelial lymphocyte (γδ IEL) compartments exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several γδ IEL compartments depends upon epithelial Btnl / BTNL (butyrophilin-like) genes, which are members of the B7 -superfamily of T cell co-stimulators. Here we show that Btnl/BTNL responsiveness is mediated by germline-encoded motifs within the cognate TCRVγ chains of mouse and human γδ IEL. This contrasts with diverse antigen recognition by clonally-restricted complementarity-determining regions (CDRs) 1-3 of TCRγδ. Hence, TCRγδ intrinsically combines innate and adaptive immunity by utilizing spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone-specific ligands. The broader implications for antigen receptor biology are considered.