T-cell receptors were first identified by using monoclonal antibodies that bound to a single cloned T-cell line: such antibodies either specifically inhibit antigen recognition by the clone or specifically activate it by mimicking the antigen (see Appendix I, Section A-20). These clonotypic antibodies were then used to show that each T cell bears about 30,000 identical antigen receptors on its surface, each receptor consisting of two different polypeptide chains, termed the T-cell receptor α (TCRα) and β (TCRβ) chains. Each chain of the α:β heterodimer is composed of two Ig domains, and the two chains are linked by a disulfide bond, similar to the structure of the Fab fragment of an immunoglobulin molecule (Fig. 4.13). α:β heterodimers account for antigen recognition by most T cells. A minority of T cells bear an alternative, but structurally similar, receptor made up of a different pair of polypeptide chains designated γ and δ. The γ:δ T-cell receptors seem to have different antigen-recognition properties from the α:β T-cell receptors, and the functions of γ:δ T cells in immune responses are still being clarified as the various ligands they recognize are identified (see Section 6-20). In the rest of this chapter and elsewhere in the book we use the term T-cell receptor to mean the α:β receptor, except where specified otherwise. Both types of T-cell receptors differ from the membrane-bound immunoglobulin that serves as the B-cell receptor in two main ways. A T-cell receptor has only one antigen-binding site, whereas a B-cell receptor has two, and T-cell receptors are never secreted, whereas immunoglobulins can be secreted as antibodies.
Further insights into the structure and function of the α:β T-cell receptor came from studies of cloned cDNA encoding the receptor chains. The amino acid sequences predicted from the cDNA showed that both chains of the T-cell receptor have an amino-terminal variable (V) region with sequence homology to an immunoglobulin V domain, a constant (C) region with homology to an immunoglobulin C domain, and a short stalk segment containing a cysteine residue that forms the interchain disulfide bond (Fig. 4.14). Each chain spans the lipid bilayer by a hydrophobic transmembrane domain, and ends in a short cytoplasmic tail. These close similarities of T-cell receptor chains to the heavy and light immunoglobulin chains first enabled prediction of the structural resemblance of the T-cell receptor heterodimer to a Fab fragment of immunoglobulin.
The three-dimensional structure of the T-cell receptor determined by X-ray crystallography in Fig. 4.15a shows that T-cell receptor chains fold in much the same way as the regions comprising the Fab fragment in Fig. 4.1a.
Fig. 4.14 Structure of the T-cell receptor. The T-cell receptor heterodimer is composed of two transmembrane glycoprotein chains, α and β. The extracellular portion of each chain consists of two domains, resembling immunoglobulin V and c domains, respectively. Both chains have carbohydrate side chains attached to each domain. A short stalk segment, analogous to an immunoglobulin hinge region, connects the ig-like domains to the membrane and contains the cysteine residue that forms the interchain disulfide bond. The transmembrane helices of both chains are unusual in containing positively charged (basic) residues within the hydrophobic transmembrane segment. The α chain carries two such residues; the β chain has one.
Antigen recognition by T cells. 153