Structure of the Vδ domain of a human γδ T-cell antigen receptor

Antigen recognition by T lymphocytes is mediated by cell-surface glycoproteins known as T-cell antigen receptors (TCRs). These are composed of alpha and beta, or gamma and delta, polypeptide chains with variable (V) and constant (C) regions, In contrast to alpha beta TCRs, which recognize antigen only as peptide fragments bound to molecules of the major histocompatibility complex (MHC), gamma delta TCRs appear to recognize proteins directly, without antigen processing, and to recognize MHC molecules independently of the bound peptide(1-4). Moreover, small phosphate-containing non-peptide compounds have also been identified as ligands far certain gamma delta T cells(5,6). These studies indicate that antigen recognition by gamma delta TCRs may be fundamentally different from that by alpha beta TCRs. The three-dimensional structures of several ap TCRs and TCR fragments(7-10), and their complexes with peptide-MHC or superantigens(9-11), have been determined. Here we report the crystal structure of the V delta domain of a human gamma delta TCR at 1.9 Angstrom resolution. A comparison with antibody and alpha beta TCR V domains reveals that the framework structure of V delta more closely resembles that of VH than of V alpha; V beta or VL (where H and L refer to heavy and light chains), whereas the relative positions and conformations of its complementarity-determining regions (CDRs) share features of both V alpha and VH. These results provide the first direct evidence that gamma delta TCRs are structurally distinct from alpha beta TCRs and, together with the observation that thr CDR3 length distribution of TCR delta chains is similar to that of immunoglobulin heavy chains(12), are consistent with functional studies suggesting that recognition of certain antigens by gamma delta TCRs may resemble antigen recognition by antibodies(1-3).