4-11. The T-cell receptor loci comprise sets of gene segments and are rearranged by the same enzymes as the immunoglobulin loci

Like immunoglobulin heavy and light chains, T-cell receptor α and β chains each consist of a variable (V) amino-terminal region and a constant (C) region (see Section 3-10). The organization of the TCRα and TCRβ loci is shown in Fig. 4.11. The organization of the gene segments is broadly homologous to that of the immunoglobulin gene segments (see Sections 4-2 and 4-3). The TCRα locus, like those for the immunoglobulin light chains, contains V and J gene segments (V_α and J_α). The TCRβ locus, like that for the immunoglobulin heavy-chain, contains D gene segments in addition to V_β and J_β gene segments.

Figure 4.11

The germline organization of the human T-cell receptor α and β loci. The arrangement of the gene segments resembles that at the immunoglobulin loci, with separate variable (V), diversity (D), joining (J) gene segments, and constant (C) (more...)

The T-cell receptor gene segments rearrange during T-cell development to form complete V-domain exons (Fig. 4.12). T-cell receptor gene rearrangement takes place in the thymus; the order and regulation of the rearrangements will be dealt with in detail in Chapter 7. Essentially, however, the mechanics of gene rearrangement are similar for B and T cells. The T-cell receptor gene segments are flanked by heptamer and nonamer recombination signal sequences (RSSs) that are homologous to those flanking immunoglobulin gene segments (see Section 4-4 and Fig. 4.5) and are recognized by the same enzymes. 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 lymphocytes altogether (see Section 4-5). A further shared feature of immunoglobulin and T-cell receptor gene rearrangement is the presence of P- and N-nucleotides in the junctions between the V, D, and J gene segments of the rearranged TCRβ gene. In T cells, P- and N-nucleotides are also added between the V and J gene segments of all rearranged TCRα genes, whereas only about half 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 (see Section 4-8 and Fig. 4.13).

Figure 4.12

T-cell receptor α- and β-chain gene rearrangement and expression. The TCRα- and β-chain genes are composed of discrete segments that are joined by somatic recombination during development of the T cell. Functional α- (more...)

Figure 4.13

The numbers 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 (more...)

The main differences between the immunoglobulin genes and those encoding T-cell receptors reflect the fact that 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 recognition. Thus, the C regions of the TCRα and TCRβ loci are much simpler than those of the immunoglobulin heavy-chain locus. There is only one C_α gene and, although there are two C_β genes, they are very closely homologous and there is no known functional distinction between their products. The T-cell receptor C-region genes encode only transmembrane polypeptides.

4-12. T-cell receptors concentrate diversity in the third hypervariable region

The extent and pattern of variability in T-cell receptors and immunoglobulins reflect the distinct nature of their ligands. Whereas the antigen-binding sites of immunoglobulins must conform to the surfaces of an almost infinite variety of different antigens, and thus come in a wide variety of shapes and chemical properties, the ligand for the T-cell receptor is always a peptide bound to an MHC molecule. The antigen-recognition sites of T-cell receptors would therefore be predicted to have a less variable shape, with most of the variability focused on the bound antigenic peptide occupying the center of the surface in contact with the receptor.

In spite of differences in the sites of variability, the three-dimensional structure of the antigen-recognition site of a T-cell receptor looks much like that of an antibody molecule (see Sections 3-11 and 3-7, respectively). In an antibody, the center of the antigen-binding site is formed by the CDR3s of the heavy and light chains. The structurally equivalent third hypervariable loops (CDR3s) of the T-cell receptor α and β chains, to which the D and J gene segments contribute, also form the center of the antigen-binding site of a T-cell receptor; the periphery of the site consists of the equivalent of the CDR1 and CDR2 loops, which are encoded within the germline V gene segments for the α and β chains.

T-cell receptor loci have roughly the same number of V gene segments as do the immunoglobulin loci, but only B cells diversify rearranged V-region genes by somatic hypermutation. Thus, diversity in the CDR1 and CDR2 loops that comprise the periphery of the antigen-binding site will be far greater among antibody molecules than among T-cell receptors. This is in keeping with the fact that the CDR1 and CDR2 loops of a T-cell receptor will mainly contact the relatively less variable MHC component of the ligand rather than the highly variable peptide component (Fig. 4.14).

Figure 4.14

The most variable parts of the T-cell receptor interact with the peptide bound to an MHC molecule. The positions of the CDR loops of a T-cell receptor are shown as the colored tubes in this figure superimposing onto the MHC:peptide complex. The CDR1 loops (more...)

The structural diversity of T-cell receptors is mainly attributable to combinatorial and junctional diversity generated during the process of gene rearrangement. It can be seen from Fig. 4.13 that the variability in T-cell receptor chains is focused on the junctional region encoded by V, D, and J gene segments and modified by P- and N-nucleotides. The TCRα locus contains many more J gene segments than either of the immunoglobulin light-chain loci: in humans, 61 J_α gene segments are distributed over about 80 kb of DNA, whereas immunoglobulin light-chain loci have only five J gene segments at most (see Fig. 4.13). Because the TCRα locus has so many J gene segments, the variability generated in this region is even greater for T-cell receptors than for immunoglobulins. This region encodes the CDR3 loops in immunoglobulins and T-cell receptors that form the center of the antigen-binding site. Thus, the center of the T-cell receptor will be highly variable, whereas the periphery will be subject to relatively little variation.

4-13. γ:δ T-cell receptors are also generated by gene rearrangement

A minority of T cells bear T-cell receptors composed of γ and δ chains (see Section 3-19). The organization of the TCRγ and TCRδ loci (Fig. 4.15) resembles that of the TCRα and TCRβ loci, although there are important differences. The cluster of gene segments encoding the δ chain is found entirely within the TCRα locus, between the V_α and the J_α gene segments. Because all V_α gene segments are oriented such that rearrangement will delete the intervening DNA, any rearrangement at the α locus results in the loss of the δ locus. There are substantially fewer V gene segments at the TCRγ and TCRδ loci than at either the TCRα or TCRβ loci or at any of the immunoglobulin loci. Increased junctional variability in the δ chains may compensate for the small number of V gene segments and has the effect of focusing almost all of the variability in the γ:δ receptor in the junctional region. As we have seen, the amino acids encoded by the junctional regions lie at the center of the T-cell receptor binding site.

Figure 4.15

The organization of the T-cell receptor γ- and δ-chain loci in humans. The TCRγ and TCRδ loci, like the TCRα and TCRβ loci, have discrete V, D, and J gene segments, and C genes. Uniquely, the locus encoding the (more...)

T cells bearing γ:δ receptors are a distinct lineage of T cells whose functions are at present unknown. The ligands for these receptors are also largely unknown (see Section 3-19). Some γ:δ T-cell receptors appear to be able to recognize antigen directly, much as antibodies do, without the requirement for presentation by an MHC molecule or processing of the antigen. Detailed analysis of the rearranged V regions of γ:δ T-cell receptors shows that they resemble the V regions of antibody molecules more than they resemble the V regions of α:β T-cell receptors.

4-14. Somatic hypermutation does not generate diversity in T-cell receptors

When we discussed the generation of antibody diversity in Section 4-9, we saw that somatic hypermutation increases the diversity of all three complementarity-determining regions of both immunoglobulin chains. Somatic hypermutation does not occur in T-cell receptor genes, so that variability of the CDR1 and CDR2 regions is limited to that of the germline V gene segments. All the diversity in T-cell receptors is generated during rearrangement and is consequently focused on the CDR3 regions.

Why T-cell and B-cell receptors differ in their abilities to undergo somatic hypermutation is not clear, but several explanations can be suggested on the basis of the functional differences between T and B cells. Because the central role of T cells is to stimulate both humoral and cellular immune responses, it is crucially important that T cells do not react with self proteins. T cells that recognize self antigens are rigorously purged during development (see Chapter 7) and the absence of somatic hypermutation helps to ensure that somatic mutants recognizing self proteins do not arise later in the course of immune responses. This constraint does not apply with the same force to B-cell receptors, as B cells usually require T-cell help to secrete antibodies. A B cell whose receptor mutates to become self reactive would, under normal circumstances, fail to make antibody for lack of self-reactive T cells to provide this help (see Chapter 9).

A further argument is that T cells already interact with a self component, namely the MHC molecule that makes up the major part of the ligand for the receptor, and thus might be unusually prone to developing self-recognition capability through somatic hypermutation. In this case, the converse argument can also be made: because T-cell receptors must be able to recognize self MHC molecules as part of their ligand, it is important to avoid somatic mutation that might result in the loss of recognition and the consequent loss of any ability to respond. However, the strongest argument for this difference between immunoglobulins and T-cell receptors is the simple one that somatic hypermutation is an adaptive specialization for B cells alone, because they must make very high-affinity antibodies to capture toxin molecules in the extracellular fluids. We will see in Chapter 10 that they do this through somatic hypermutation followed by selection for antigen binding.

Summary

T-cell receptors are structurally similar to immunoglobulins and are encoded by homologous genes. T-cell receptor genes are assembled by somatic recombination from sets of gene segments in the same way as are the immunoglobulin genes. Diversity is distributed differently in immunoglobulins and T-cell receptors; the T-cell receptor loci have roughly the same number of V gene segments but more J gene segments, and there is greater diversification of the junctions between gene segments during gene rearrangement. Moreover, functional T-cell receptors are not known to diversify their V genes after rearrangement through somatic hypermutation. This leads to a T-cell receptor in which the highest diversity is in the central part of the receptor, which contacts the bound peptide fragment of the ligand.