The crystallographic structure of a γ:δ T-cell receptor reveals that, as expected, it is similar in shape to α:β T-cell receptors. Figure 4.31 shows a crystal structure of a γ:δ T-cell receptor complex bound to one of the nonclassical MHC class I molecules mentioned above, called T22. This structure shows that the overall orientation of the γ:δ T-cell receptor with the MHC molecule is strikingly different from that of an α:β T-cell receptor, in that it interacts primarily with one end of the T22 molecule. However, the CDR3 regions of the γ:δ T-cell receptor still play a critical role in recognition, similar to that of antibodies and of α:β T-cell receptors. Further, the CDR3 of the γ:δ T-cell receptor is longer than either of these other two antigen receptors, and this could have implications toward the type of ligand that the γ:δ T-cell receptor recognizes, as there is enormous combinatorial diversity from the CDR3 within the γ:δ T-cell receptor repertoire. We will return to discuss further the ligands and the development of γ:δ T cells in Chapters 6 and 8.
Summary.
The receptor for antigen on most T cells, the α:β T-cell receptor, is composed of two protein chains, TCRα and TCRβ, and resembles in many respects a single Fab fragment of immunoglobulin. α:β T-cell receptors are always membrane-bound and recognize a composite ligand of a peptide antigen bound to an MHC molecule. Each MHC molecule binds a wide variety of different peptides, but the different variants of MHC each preferentially recognize sets of peptides with particular sequences and physical features. The peptide antigen is generated intracellularly, and is bound stably in a peptide-binding cleft on the surface of the MHC molecule. There are two classes of MHC molecules, and these are bound in their nonpolymorphic domains by CD8 and CD4 molecules that distinguish two different functional classes of α:β T cells. CD8 binds MHC class I molecules and can bind simultaneously to the same peptide:MHC class I complex being recognized by a T-cell receptor, thus acting as a co-receptor and enhancing the T-cell response; CD4 binds MHC class II molecules and acts as a co-receptor for T-cell receptors that recognize peptide:MHC class II ligands. A T-cell receptor interacts directly both with the antigenic peptide
Fig. 4.31 Structures of γ:δ T-cell receptor bound to the nonclassical MHC class I molecule T22. The γ:δ T-cell receptor has a similar overall structure to the α:β T-cell receptor and the fab fragment of an immunoglobulin. The cδ domain is more like an immunoglobulin domain than is the corresponding cα domain of the α:β T-cell receptor. in this structure, the overall orientation of the γ:δ T-cell receptor with respect to the nonclassical Mhc molecule T22 is very different from the orientation of an α:β T-cell receptor with either Mhc class i or class ii molecules. Rather than lying directly over the peptide-binding groove, the γ:δ T-cell receptor is engaged with one end much more than the other; this is consistent with a lack of peptide contact and absence of Mhc-restricted recognition.
and with polymorphic features of the MHC molecule that displays it, and this dual specificity underlies the MHC restriction of T-cell responses. A second type of T-cell receptor, composed of a γand a δ chain, is structurally similar to the α:β T-cell receptor, but it binds to different ligands, including nonpeptide ligands, nonpolymorphic nonclassical MHC molecules, and certain lipids. The receptor is thought not to be MHC-restricted and is found on a minority population of lymphoid and intraepithelial T cells, the γ:δ T cells.