interspersed with the Vα genes but are located primarily in the 3ʹ region of the locus. Because all Vα 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 (Fig. 5.18). There are substantially fewer V gene segments at the TCRγ and TCRδ loci than at either the TCRα or TCRβ loci or 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 the variability in the γ:δreceptor in the junctional region. As we have seen for the α:β T-cell receptors, the amino acids encoded by the junctional regions lie at the center of the T-cell receptor binding site. T cells bearing γ:δ receptors are a distinct lineage of T cells, and as discussed in Chapter 4, some γ:δ T cells recognize nonclassical MHC class I molecules and other molecules whose expression may be an indication of cellular damage or infection. As we saw in Section 4-20, the CDR3 of a γ:δ T cell is frequently longer than the CDR3 in an α:β T-cell receptor; this permits the CDR of γ:δ T cell receptors to interact directly with ligand and also contributes to the great diversity of these receptors. We will discuss the regulation of the fate choice between the α:βand γ:δ T-cell lineages in Chapter 8.
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 that the immunoglobulin genes are. Diversity is, however, distributed differently in immunoglobulins and T-cell receptors: the T-cell receptor loci have roughly the same number of V gene segments as the immunoglobulin loci but more J gene segments, and there is greater diversification of the junctions between gene segments during the process of gene rearrangement. Thus, the greatest diversity of the T-cell receptor is in the central part of the receptor, within the CDR3, which in the case of α:β T-cell receptors contacts the bound peptide fragment of the ligand. Most of the diversity among γ:δ T-cell receptors is also within the CDR3, which is frequently longer than the CDR3 of α:β T-cell receptors and can also directly interact with ligands recognized by the γ:δ T cells.
Structural variation in immunoglobulin constant regions.
This chapter so far has focused on the mechanisms of assembly of the V regions for immunoglobulins and T-cell receptors. We now turn to the C regions. The C regions of T-cell receptors act only to support the V regions and anchor the receptor into the membrane, and they do not vary after assembly of a complete receptor gene. Immunoglobulins, in contrast, can be made as both a trans-membrane receptor and a secreted antibody, and they can be made in several different classes, depending on the different C regions used by the heavy chain. The light-chain C regions (CL) provide only structural attachment for V regions, and there seem to be no functional differences between λand κ light chains. The heavy-chain locus encodes different C regions (CH) that are present as separate genes located downstream of the V-region segments. Initially, naive B cells use only the first two of these, the Cμ and Cδ genes, which are expressed along with the associated assembled V-region sequence to produce transmembrane IgM and IgD on the surface of the naive B cell.
In this section, we introduce the different heavy-chain isotypes and discuss some of their special properties as well as the structural features that distinguish the CH regions of antibodies of the five major classes. We explain how