The mechanism by which B-cell antigen receptors are generated is such a powerful means of creating diversity that it is not surprising that the antigen receptors of T cells bear structural resemblances to immunoglobulins and are generated by the same mechanism. In this part of the chapter we describe the organization of the T-cell receptor loci and the generation of the genes for the individual T-cell receptor chains.
5-9 The T-cell receptor gene segments are arranged in a similar pattern to immunoglobulin gene segments and are rearranged by the same enzymes.
Like immunoglobulin light and heavy chains, T-cell receptor (TCR) α and β chains each consist of a variable (V) amino-terminal region and a constant (C) region (see Section 4-10). The organization of the TCRα and TCRβ loci is shown in Fig. 5.12. The organization of the gene segments is broadly homologous to that of the immunoglobulin gene segments (see Sections 5-2 and 5-3). The TCRα locus, like the loci of the immunoglobulin light chains, contains V and J gene segments (Vα and Jα). The TCRβ locus, like the locus of the immunoglobulin heavy chain, contains D gene segments in addition to Vβ and Jβ gene segments. The T-cell receptor gene segments rearrange during T-cell development to form complete V-domain exons (Fig. 5.13). T-cell receptor gene rearrangement takes place in the thymus; the order and regulation of the rearrangements are dealt with in detail in Chapter 8. Essentially, however, the mechanics of gene rearrangement are similar for B and T cells. The T-cell receptor gene segments are flanked by 12-bp and 23-bp spacer recombination signal sequences (RSSs) that are homologous to those flanking immunoglobulin
Fig. 5.12 The germline organization of the human T-cell receptor α and β loci.
The arrangement of the gene segments for the T-cell receptor resembles that at the immunoglobulin loci, with separate variable (V), diversity (D), and joining (J) gene segments, and constant (C) genes. The TCRα locus (chromosome 14) consists of 70–80 Vα gene segments, each preceded by an exon encoding the leader sequence (L). How many of these Vα gene segments are functional is not known exactly. A cluster of 61 Jα gene segments is located a considerable distance from the Vα gene segments. The Jα gene segments are followed by a single C gene, which contains separate exons for the constant and hinge domains and a single exon encoding the transmembrane and cytoplasmic regions (not shown). The TCRβ locus (chromosome 7) has a different organization, with a cluster of 52 functional Vβ gene segments located distant from two separate clusters that each contain a single D gene segment together with six or seven J gene segments and a single C gene. Each TCRβ C gene has separate exons encoding the constant domain, the hinge, the transmembrane region, and the cytoplasmic region (not shown). The TCRα locus is interrupted between the J and V gene segments by another T-cell receptor locus—the TCRδ locus (not shown here; see Fig. 5.17).