Each germline TCR locus is arranged in a very similar way to the Ig loci described earlier, with a 5′ cluster of several V gene segments, followed by D segments (in the β and δ loci only), followed by a cluster of J segments, all upstream of C region genes (Fig. 1). In the human β locus, there are about 50 V, 2 D, and 12 J gene segments, and in the α locus there are 45 V and 50 J segments. The γ and δ loci overall have fewer gene segments than the α and β loci, with a total of only seven V genes.
Fig1. Germline organization of human TCR loci. The human TCR β, α, γ, and δ chain loci are shown, as indicated. Exons and introns are not drawn to scale, and nonfunctional pseudogenes are not shown. Each C gene is shown as a single box but is composed of several exons, as illustrated for Cβ1. Gene segments are indicated as follows: L, Leader (often called signal sequence); V, variable; D, diversity; J, joining; C, constant; enh, enhancer; sil, silencer (sequences that regulate TCR gene transcription).
Upstream of each TCR V gene segment is an exon that encodes a leader peptide, and upstream of each leader exon is a promoter for each V gene segment. In the TCR β and δ proteins, the V domain is encoded by the V, D, and J gene segments, and in the TCR α and γ proteins, the V domain is encoded by the V and J gene segments. In all these V domains, CDR1 and CDR2 are encoded by germline sequences within V gene segments. CDR3 in each TCR β and TCR δ chain is encoded by a few terminal residues of the V segment, a D and a J segment as well as nongermline junctional sequences that are added between the V, D, and J segments during V(D)J recombination. CDR3 in each α and γ chain is encoded by a few terminal residues from the V segments, and nongermline junctional sequences between the V and J segment and by the J segment itself. There are two C genes in each of the human TCR β and TCR γ loci, but only one is used in any T-cell clone, and each of the two has its own associated 5′ cluster of J segments. There is only one C gene in each of the α and δ loci. Each TCR C region gene is composed of four exons encoding the extracellular C region Ig domain, a short hinge region, the transmembrane segment, and the cytoplasmic tail.
The relationship of the TCR gene segments and the corresponding portions of TCR proteins that they encode is shown in Fig. 2B.
Fig2. Domains of immunoglobulin (Ig) and TCR proteins. The domains of Ig heavy and light chains are shown in (A) and the domains of TCR α and β chains are shown in (B). The relationships between the Ig and TCR gene segments and the domain structure of the antigen receptor polypeptide chains are indicated. The V and C regions of each polypeptide are encoded by different gene segments. The locations of intrachain and interchain disulfide bonds (S-S) are approximate. Areas in the dashed boxes are the hypervariable (complementarity-determining) regions. In the Ig µ chain and the TCR α and β chains, transmembrane (TM) and cytoplasmic (CYT) domains are encoded by separate exons. N and C refer to amino and carboxy termini, respectively. C, Constant; D, diversity, J, joining; V, variable.
