The TCRαand β-chain genes are composed of discrete segments that are joined by somatic recombination during development of the T cell. Functional αand β-chain genes are generated in the same way that complete immunoglobulin genes are created. For the α chain (upper part of figure), a Vα gene segment rearranges to a Jα gene segment to create a functional V-region exon. Transcription and splicing of the VJα exon to Cα generates the mRNA that is translated to yield the T-cell receptor α-chain protein. For the β chain (lower part of figure), like the immunoglobulin heavy chain, the variable domain is encoded in three gene segments, Vβ, Dβ, and Jβ. Rearrangement of these gene segments generates a functional VDJβ V-region exon that is transcribed and spliced to join to Cβ; the resulting mRNA is translated to yield the T-cell receptor β chain. The α and β chains pair soon after their synthesis to yield the α:β T-cell receptor heterodimer. Not all J gene segments are shown, and the leader sequences preceding each V gene segment are omitted for simplicity.
Fig. 5.14 Recombination signal sequences flank T-cell receptor gene segments. As in the immunoglobulin gene loci (see Fig. 5.6), the individual gene segments at the TCRα and TCRβ loci are flanked by heptamer–spacer–nonamer recombination signal sequences (RSSs). RSS motifs containing 12-bp spacers are depicted here as orange arrowheads, and those containing 23-bp spacers are shown in purple. Joining of gene segments almost always follows the 12/23 rule. Because of the disposition of heptamer and nonamer RSSs in the TCRβ and TCRδ loci, direct Vβ to Jβ joining is in principle allowed by the 12/23 rule (unlike in the immunoglobulin heavy-chain gene), although this occurs very rarely owing to other types of regulation.
Fig. 5.13 T-cell receptor αand β-chain gene rearrangement and expression.
gene segments (Fig. 5.14; see Section 5-4) and are recognized by the same enzymes. The DNA circles resulting from gene rearrangement (see Fig. 5.7) are known as T-cell receptor excision circles (TRECs) and are used as markers for T cells that have recently emigrated from the thymus. All known defects in genes that control V(D)J recombination affect T cells and B cells equally, and animals with these genetic defects lack functional B and T lymphocytes altogether (see Section 5-5). A further shared feature of immunoglobulin and T-cell receptor gene rearrangement is the presence of Pand N-nucleotides in the junctions between the V, D, and J gene segments of the rearranged TCRβ gene. In T cells, Pand N-nucleotides are also added between the V and J gene segments of all rearranged TCRα genes, whereas only about half of the V–J joints in immunoglobulin light-chain genes are modified by N-nucleotide addition, and these are often left without any P-nucleotides as well (Fig. 5.15; see Section 5-8).
The main differences between the immunoglobulin genes and those encoding T-cell receptors reflect the differences in how B cells and T cells function. All the effector functions of B cells depend upon secreted antibodies whose different heavy-chain C-region isotypes trigger distinct effector mechanisms. The effector functions of T cells, in contrast, depend upon cell–cell contact and are not mediated directly by the T-cell receptor, which serves only for antigen
Fig. 5.15 The number of human T-cell receptor gene segments and the sources of T-cell receptor diversity compared with those of immunoglobulins. Note that only about half of human κ chains contain N-nucleotides. Somatic hypermutation as a source of diversity is not included in this figure because it does not occur in T cells.