Barry A. Fields

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 α and β, or γ and δ, polypeptide chains with variable (V) and constant (C) regions. In contrast to αβ TCRs, which recognize antigen only as peptide fragments bound to molecules of the major histocompatibility complex (MHC), γδ TCRs appear to recognize proteins directly, without antigen processing, and to recognize MHC molecules independently of the bound peptide. Moreover, small phosphate-containing non-peptide compounds have also been identified as ligands for certainγδ T cells,. These studies indicate that antigen recognition by γδ TCRs may be fundamentally different from that by αβ TCRs. The three-dimensional structures of several αβ TCRs and TCR fragments, and their complexes with peptide–MHC or superantigens, have been determined. Here we report the crystal structure of the Vδ domain of a human γδ TCR at 1.9u2009Å resolution. A comparison with antibody and αβ TCR V domains reveals that the framework structure of Vδ more closely resembles that of VHthan of Vα, Vβ or VL(where H and L refer to heavy and light chains), whereas therelative positions and conformations of its complementarity-determining regions (CDRs) share features of both Vα and VH. These results provide the first direct evidence that γδ TCRs are structurally distinct from αβ TCRs and, together with the observation that the CDR3 length distribution of TCR δ chains is similar to that of immunoglobulin heavy chains, are consistent with functional studies suggesting that recognition of certain antigens by γδ TCRs may resemble antigen recognition by antibodies.

Structure and function of the T-cell receptor: insights from X-ray crystallography

Abstract The long awaited information on the three-dimensional structure of the T-cell antigen receptor (TCR) has recently been reported. The structure of a TCR β chain and that of a Vα homodimer confirm predictions that TCR V and C domains closely resemble their immunoglobulin counterparts. However, as described here by Barry Fields and Roy Mariuzza, structural features have also been identified that are unique to the TCR and possibly important for peptide-MHC recognition and signal transrduction.

Protein motion and lock and key complementarity in antigen-antibody reactions

Antibodies possess a highly complementary combining site structure to that of their specific antigens. In many instances their reactions are driven by enthalpic factors including, at least in the case of the reaction of monoclonal antibody D1.3 with lysozyme, enthalpy of solvation. They require minor structural rearrangements, and their equilibrium association constants are relatively high (10(7)-10(11) M-1). By contrast, in an idiotope--anti-idiotope (antibody-antibody) reaction, which is entropically driven, the binding equilibrium constant is only 1.5 x 10(5) M-1 at 20 degrees C. This low value results from a slow association rate (10(3) M-1 s-1) due to a selection of conformational states that allow one of the interacting molecular surfaces (the idiotope on antibody D1.3) to become complementary to that of the anti-idiotopic antibody. Thus, antibody D1.3 reacts with two different macromolecules: with its specific antigen, hen egg lysozyme, and with a specific anti-idiotopic antibody. Complementarity with lysozyme is closer to a lock and key model and results in high affinity (2-4 x 10(8) M-1). That with the anti-idiotopic antibody involves conformational changes at its combining site and it results in a lower association constant (1.5 x 10(5) M-1). Thus, an induced fit mechanism may lead to a broadening of the binding specificity but with a resulting decrease in the intrinsic binding affinity which may weaken the physiological function of antibodies.

Structure of the V|[delta]| domain of a human |[gamma]||[delta]| 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 α and β, or γ and δ, polypeptide chains with variable (V) and constant (C) regions. In contrast to αβ TCRs, which recognize antigen only as peptide fragments bound to molecules of the major histocompatibility complex (MHC), γδ TCRs appear to recognize proteins directly, without antigen processing, and to recognize MHC molecules independently of the bound peptide. Moreover, small phosphate-containing non-peptide compounds have also been identified as ligands for certainγδ T cells,. These studies indicate that antigen recognition by γδ TCRs may be fundamentally different from that by αβ TCRs. The three-dimensional structures of several αβ TCRs and TCR fragments, and their complexes with peptide–MHC or superantigens, have been determined. Here we report the crystal structure of the Vδ domain of a human γδ TCR at 1.9u2009Å resolution. A comparison with antibody and αβ TCR V domains reveals that the framework structure of Vδ more closely resembles that of VHthan of Vα, Vβ or VL(where H and L refer to heavy and light chains), whereas therelative positions and conformations of its complementarity-determining regions (CDRs) share features of both Vα and VH. These results provide the first direct evidence that γδ TCRs are structurally distinct from αβ TCRs and, together with the observation that the CDR3 length distribution of TCR δ chains is similar to that of immunoglobulin heavy chains, are consistent with functional studies suggesting that recognition of certain antigens by γδ TCRs may resemble antigen recognition by antibodies.