Genomic organization of the human T-cell antigen-receptor alpha/delta locus.

Abstract

Two clusters of overlapping cosmid clones comprising about 100 kilobases (kb) at the human T-cell antigen-receptor a/6 locus were isolated from a genomic library. The structure of the germ-line Vis1 variable gene segment was determined. V1al is located 8.5 kb downstream of the Val3.1 gene segment, and both V segments are arranged in the same transcriptional orientation. The Vd7.1 segment is located between V81 and the Li, J;, Cc, region (containing the diversity, joining, and constant gene segments). Thus, Vs and V% segments -are interspersed along the chromosome. The germ-line organization of the L 2, Jr,1, and Jr,2 segments was determined. Linkage of Cc, to the J. region was established by identification of J,, segments within 20 kb downstream of C8.The organization of the locus was also analyzed by fieldinversion gel electrophoresis. The unrearranged Vsl and D8, Jl, Cat regions are quite distant from each other, apparently separated by a minimum of 175-180 kb.In addition to T-cell antigen receptor (TCR) a43 (a heterodimer ofpolypeptides termed a and f3), a second TCR, 'y8, has recently been identified (1). Whereas TCR a,3 is expressed on the majority of peripheral blood T lymphocytes, TCR y5 is expressed on a small fraction of peripheral blood TYlymphocytes, as well as on some thymic T cells and dendritic epidermal cells. The-function of the lymphocytes that bear TCR y5 is unknown.The genes encoding the TCR a, /3, -y, and 8 polypeptides are all assembled from multiple gene segments that rearrange to form a functional gene during T-cell differentiation (1-3). The diversity of TCR a/3 is immense due to the use of large numbers of variable (V) and joining (J) segments, and in the case of TCR 3, diversity (D) segments as well. TCR y8 apparently displays a more limited repertoire of germ-line V and J elements but nevertheless displays extraordinary diversity at the V-J junction. This is due in part to the novel use of two Do elements that can be incorporated together into the junctional region (4-6).Whereas the TCR a, ,/, and ygenes are all unlinked, studies in mice (7), as well as preliminary studies in humans (8-10), indicate that the TCR 8 gene lies within the TCR a locus, upstream ofthe estimated 50-100J, segments and between V,, and J,,,. However, rearrangement at this locus appears to be highly regulated. Whereas TCR 8 genes rearrange early in thymic ontogeny, TCR a genes rearrange much later. Further, the utilization of V segments appears to be selective.For example, to date the human V.] segment has only been observed to be utilized in TCR y8 lymphocytes, whereas V. segments have not been found to be similarly utilized. The details of the organization of the TCR a/8 locus may shed light on the manner in which rearrangements at this locus are controlled. To better understand the structure of the germline elements that contribute to the diversity ofTCR 8, as well as the organization of these elements with respect to those of TCR a, we have undertaken an analysis of the germ-line organization of the T...

Recombinative events of the T cell antigen receptor delta gene in peripheral T cell lymphomas.

“…The TCR 6 locus, which has been recently characterized (13)(14)(15)(16)(17)(18)(19)(20)(21)(22), is located within the TCR a locus on chromosome 14 and is flanked by Va segments on its 5' side and by Ja segments on its 3' side. To date, one Cb, three J6, three DS, and six VS segments have been reported (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

A δ T-Cell Receptor Deleting Element Transgenic Reporter Construct Is Rearranged in αβ but not γδ T-Cell Lineages

“…While heavy and light immunoglobulin chains, as well as TCR ␤ and ␥ chains, have distinct chromosomal localizations (30, 31), the TCR ␦ chain locus is contained within the much larger TCR ␣ chain locus on chromosome 14 in both mice and humans (9,22,24,36,45,49). This unique organization of TCR loci poses interesting questions concerning the use of these distinct receptor chains.…”

“…Most mature T cells have ␣ and ␤ chains paired with CD3, while T-cell receptor (TCR) ␥ and ␦ chains are associated with CD3 on quite different T cells (1,5,10,21,32,38). These two types of T cells have different tissue distributions and appear to have different functions (2,4,43).While heavy and light immunoglobulin chains, as well as TCR ␤ and ␥ chains, have distinct chromosomal localizations (30, 31), the TCR ␦ chain locus is contained within the much larger TCR ␣ chain locus on chromosome 14 in both mice and humans (9,22,24,36,45,49). This unique organization of TCR loci poses interesting questions concerning the use of these distinct receptor chains.…”

The hLEF/TCF-1 alpha HMG protein contains a context-dependent transcriptional activation domain that induces the TCR alpha enhancer in T cells.

“…The polymorphic TCR subunit genes are composed of variable (VI, diversity (D), and joining (l) gene segments that rearrange in somatic cells upstream of a constant (C) gene segment. Nearly 100 Va and 50-100 ]a segments lie within 65 kb of the various Ca exons for the a-chain of the human TCR (Satyanarayana et al 1988), and expression of the Present addresses: tDepartment of Molecular Biology, University of Goteborg, Goteborg, Sweden; 2Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, California 92717 USA. 3Corresponding author.…”