HGNC Approved Gene Symbol: TRGC1
Cytogenetic location: 7p14.1 Genomic coordinates (GRCh38) : 7:38,260,088-38,265,678 (from NCBI)
T-lymphocytes recognize antigens via a mechanism that resembles that used by immunoglobulins (Igs; see 147200) produced by B cells. There are 2 main mature T-cell subtypes, those expressing alpha (see TRAC; 186880) and beta (see TRBC1; 186930) chains, and those expressing gamma and delta (see TRDC; 186810) chains. Unlike secreted Ig molecules, T-cell receptor chains are membrane bound and act through cell-cell contact. Gamma-delta T cells may also recognize antigens directly without presentation by the major histocompatibility complex. The genes encoding the T-cell receptor gamma chain are clustered on chromosome 7. The T-cell receptor gamma chain is formed when 1 of 12 variable (V) genes (see 615454), which encode the N-terminal antigen recognition domain, rearranges to a joining (J) gene to create a functional V region exon that is transcribed and spliced to a constant (C) region gene segment encoding the C-terminal portion of the molecule. Like the beta chain locus, the gamma chain locus has 2 separate clusters of genes after the V genes, each containing several J genes (see 615455) and a C gene (e.g., TRGC1). The lymphoid-specific proteins RAG1 (179615) and RAG2 (179616) direct the V(D)J recombination process in both T and B cells. Following synthesis, the gamma and delta chains pair to yield the gamma-delta T-cell receptor heterodimer (Janeway et al., 2005).
During the search for the T-cell receptor genes, Saito et al. (1984) identified in T cells another Ig-like gene, which they called gamma. The product of the rearranged gamma locus is the gamma chain, which is expressed, along with the delta chain, at the surface of a subset of T lymphocytes.
Brenner et al. (1986), Bank et al. (1986), Weiss et al. (1986), and Moingeon et al. (1986) identified the gamma chain as part of a heterodimer gamma-delta, associated with CD3, on the surface of CD3+/CD4-/CD8- peripheral T lymphocytes and thymocytes. Although some gamma-delta(+) cells displayed a cytolytic activity, their precise function remained to be elucidated.
Lefranc and Rabbitts (1985) showed that the TCRG locus comprises 2 constant region genes separated by 16 kb and that these 2 genes can undergo rearrangements, deletion of the C-gamma-1 (TRGC1) gene accompanying the rearrangements in the C-gamma-2 (TRGC2; 615450) gene. These rearrangements have been observed in all T-cell types studied, providing evidence that the TCRG gene is an excellent marker of clonality for T-cell leukemias and lymphomas.
Lefranc et al. (1986) showed that the C-gamma-1 gene has 3 exons, whereas the C-gamma-2 gene has 4 exons including a duplicated second exon. The exon 2 of C-gamma-1 encodes a cysteine residue thought to be involved in the interchain disulfide bridge, whereas the 2 duplicated exons of C-gamma-2 do not encode the cysteine residue.
Lefranc et al. (1986) demonstrated that there are no somatic mutations or D segments in the TCRG locus and that the variability is restricted to N-region diversity.
By pulsed field gel electrophoresis, Strauss et al. (1987) estimated the gamma locus to be 160 kb.
A complete picture of the organization of the TCRG variable region was given by Lefranc et al. (1989), the 14 variable genes being located upstream and shared by 2 C-gamma genes. The order of the subgroups is 5-prime--V-gamma-I--VA--V-gamma-II-- V-gamma-III--VB--V-gamma-IV--C-gamma--3-prime; the gene linkage order is 5-prime--TRGV1, V2, V3, V4, V5, V5P, V6, V7, V8, VA, V9, V10, VB, V11, JP1, JP, J1, C1, JP2, J2, C2--3-prime.
Lefranc et al. (1989) showed that all the V-gamma genes span 100 kb and demonstrated concomitantly with Fox et al. (1989) that 16 kb separate the most 3-prime variable gene (V-gamma-11) from the most 5-prime joining segment (JP1); thus, the entire locus spans about 160 kb.
For a review on the organization of the human T-cell receptor gamma genes, see Lefranc (1988) and Lefranc and Rabbitts (1989, 1990).
Janeway et al. (2005) summarized the germline organization of the human TCR-gamma locus. The TCR-gamma locus contains a cluster of 12 functional V gene segments (see 615454), each preceded by an exon encoding the leader sequence. The V gene cluster is followed by 2 separate clusters of genes. The first contains 3 J genes (see 615455) and a C gene (TRGC1), and the second contains 2 J genes and a C gene (TRGC2).
Rabbitts et al. (1985) mapped the human T-cell receptor gamma (TCRG) locus to chromosome 7 by hybridization to a panel of cell hybrids. Murre et al. (1985) and Bensmana et al. (1991) localized it to 7p15-p14 by in situ hybridization.
Gross (2013) mapped the TCR-gamma locus, which contains the TRGC1 gene, to chromosome 7p14.1 based on an alignment of the TCR-gamma locus sequence (GenBank AF159056) with the genomic sequence (GRCh37).
Kranz et al. (1985) assigned the T-cell gamma gene to mouse chromosome 13.
Forster et al. (1987) demonstrated that the sizes of the rearranged BamHI, HindIII, and EcoRI fragments detected by hybridization to a J1 probe, pH60, allow the identification of a V gene rearranged to J1 or J2. This unequivocal assignment provides an easy way to determine V-gamma usage and is clinically useful in deciding clonality of leukemia and lymphoma samples.
Triebel et al. (1988) showed that most of the gamma-delta(+) cells from the peripheral blood express a V9-JP-C1 gamma chain.
Kaufmann (1996) reviewed the function of the gamma/delta T cells. Almost all knowledge about T cells had stemmed from alpha/beta T cells. In contrast to alpha/beta T cells, which are specific for antigenic peptides presented by gene products of the major histocompatibility complex, gamma/delta T cells directly recognize proteins and even nonproteinacious phospho-ligands. Thus, the 2 types of T cells recognize antigen in a fundamentally different way and hence mitigate against the dogma of exclusive peptide-MHC recognition by T cells. The role of gamma/delta T cells in antimicrobial immunity is firmly established. The prominent residence of gamma/delta T cells in epithelial tissues and the rapid mobilization of these cells in response to infection are consistent with regulatory activities under physiologic and pathologic conditions. Kaufmann (1996) observed that, although these cells 'are a minor fraction of all T cells, they are not just uninfluential kin of alpha/beta T cells but have their unique raison d'etre.'
Brenner et al. (1987), Borst et al. (1987), Krangel et al. (1987), and Van Dongen et al. (1987) showed that the human gamma chain can be either disulfide or nondisulfide linked to the delta chain. Such a structural difference was explained by the presence or lack of key cysteine codons in the C-gamma genes.
Allison et al. (2001) described the structure of a human gamma/delta TCR from a phosphoantigen-reactive T-cell clone at 3.1-angstrom resolution. Overall, the variable (V) domains are similar in structure to those of alpha/beta TCRs; however, the constant (C) domains are markedly different. Owing to an unusually small angle between V-gamma and C-gamma domains, the orientation of the V and C regions of the gamma/delta TCR is unique compared to those of other immune system receptors, antibodies and alpha/beta TCRs, that are products of rearranging gene segments. Allison et al. (2001) noted that the complementarity-determining regions (CDRs) of the V domains exhibit a suitable binding site for phosphorylated antigens that may account for the broad antigen reactivity of peripheral blood gamma/delta T cells.
Tycko et al. (1989) suspected that intergenic joining of segments among different antigen receptor genes might occur in normal human lymphoid tissues because of the same highly conserved heptamer-nonamer sequences flanking the V-, D-, and J-region gene segments. They used PCR to check for the presence of chimeric gamma-delta T-cell receptor gene rearrangements. Chimeric rearrangements were detected in thymus, peripheral blood and tonsil. Most transcripts were appropriately spliced and showed correct open translational reading frames across the V-(D)-J junctions. The chimeric gene products are probably generated by chromosomal translocations and such hybrid genes may possibly contribute to increased diversity within the antigen receptor repertoire. The gamma and delta genes are on chromosomes 7 and 14, respectively. Balanced t(7;14)(p13;q11) chromosomal translocations have been observed at frequencies of 10(-3) to 10(-4) in phytohemagglutinin-stimulated lymphocytes from normal human peripheral blood (Welch and Lee, 1975; Hecht et al., 1975; Dewald et al., 1986).
Murre et al. (1985) found evidence of somatic rearrangement of the gamma-chain genes in T-cell leukemia cells. Furthermore, 1 of the 2 constant-region gene segments was deleted in each of the 3 T-cell leukemias studied. The 2 constant region genes are located at 7p15. This region is involved in chromosomal rearrangements in T cells from persons with ataxia-telangiectasia (208900). In the T cells of a patient with ataxia-telangiectasia, Stern et al. (1989) observed a rearrangement inv(7)(p14q35). Molecular characterization of the inversion showed that 1 breakpoint occurred in the variable region of the TCRG gene, which is consistent with localization at 7p14.
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