The structural diversity of T-cell receptors is attributable mainly to combinatorial and junctional diversity generated during the process of gene rearrangement. It can be seen from Fig. 5.15 that most of the variability in T-cell receptor chains is in the junctional regions, which are encoded by V, D, and J gene segments and modified by Pand N-nucleotides. The TCRα locus contains many more J gene segments than either of the immunoglobulin light-chain loci: in humans, 61 Jα gene segments are distributed over about 80 kb of DNA, whereas immunoglobulin light-chain loci have only 5 J gene segments at most (see Fig. 5.15). Because the TCRαlocus has so many J gene segments, the variability generated in this region is even greater for T-cell receptors than for immunoglobulins. Thus, most of the diversity resides in the CDR3 loops that contain the junctional region and form the center of the antigen-binding site.
5-11 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 4-20). The organization of the TCRγ and TCRδ loci (Fig. 5.17) 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 Vα and the Jα gene segments. Vδ genes are
Fig. 5.17 The organization of the T-cell receptor γand 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 δ chain is located entirely within the α-chain locus. The three Dδ gene segments, four Jδ gene segments, and the single δ C gene lie between the cluster of Vα gene segments and the cluster of Jα gene segments. There are two Vδ gene segments (not shown) located near the δ C gene, one just upstream of the D regions and one in inverted orientation just downstream of the C gene. In addition, there are six Vδ gene segments interspersed among the Vα gene segments. Five are shared with Vα and can be used by either locus, and one is unique to the δ locus. The human TCRγ locus resembles the TCRβ locus in having two C genes, each with its own set of J gene segments. The mouse γ locus (not shown) has a more complex organization and there are three functional clusters of γ gene segments, each containing V and J gene segments and a C gene. Rearrangement at the γ and δ loci proceeds as for the other T-cell receptor loci, with the exception that during TCRδ rearrangement two D segments can be used in the same gene. The use of two D segments greatly increases the variability of the δ chain, mainly because extra N-region nucleotides can be added at the junction between the two D gene segments as well as at the V–D and D–J junctions.