The gamma delta TCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness

T lymphocytes expressing gamma delta T cell antigen receptors (TCRs) comprise evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded gamma delta T cells with unique specificities typify adaptive immunity. Conversely, large compartments of gamma delta TCR+ intraepithelial lymphocytes (gamma delta IELs) exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several gamma delta IEL compartments depends on epithelial expression of genes encoding butyrophilin-like (Btnl (mouse) or BTNL (human)) members of the B7 superfamily of T cell co-stimulators. Here we found that responsiveness to Btnl or BTNL proteins was mediated by germline-encoded motifs within the cognate TCR variable gamma-chains (V-gamma chains) of mouse and human gamma delta IELs. This was in contrast to diverse antigen recognition by clonally restricted complementarity-determining regions CDR1-CDR3 of the same gamma delta TCRs. Hence, the gamma delta TCR intrinsically combines innate immunity and adaptive immunity by using spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone-specific ligands. The broader implications for antigen-receptor biology are considered.