The organization and sequences of the human (3-chain T-cell receptor diversity, joining, and constant region segments are described. The (3 chain of the human T-cell receptor, analogous to the mouse counterpart, consists of two distinct constant region genes =10 kilobases apart. The two constant region genes, Cpu and Cp.2, are very similar not only in sequence but also in genomic organization. The coding sequences of each of these Cp constant region genes are divided into four exons. The first two exons encode most of the extracellular constant domain. The third exon encodes a major part of the presumed transmembrane portion, and the last exon contains the cytoplasmic coding sequence as well as 3' untranslated sequences. Except for a stretch of =95 highly conserved nucleotides extending 3' of the first exon of the C region genes, little homology can be found between the intron sequences of Cpg and Cp2. A small cluster of joining region (Jp) gene segments is located ""5 kilobases upstream of each of these two constant regions. The first cluster, Jp1, contains six functional J gene segments while the second, Jp2, contains seven functional J gene segments. In addition, diversity region (Dp) gene segments are located ==600 base pairs upstream of each Jp.Recombinational signals containing highly conserved heptamer and nonamer sequences separated by 12 or 23 bases are found adjacent to all of these Dp and Jp gene segments. These signal sequences are thought to be involved in the somatic recombination processes. These results indicate that what appears to be a gene duplication event giving rise to these two distinct regions must have arisen a long time ago in the evolution of this gene locus.An essential property of the immune system is its ability to generate enormous diversity in antibody and T-cell responses. During the past several years, the genetic and molecular mechanisms responsible for the generation of antibody diversity have been elucidated (1, 2 Recently, the structure and diversity generation of the T-cell receptor (TcR) have also been studied (3, 4). The cloning of both the a-and /-chain TcR genes (5-10) has allowed direct comparisons with immunoglobulin genes to be made. Both chromosomal location (11,12) and partial DNA/protein sequence homologies (5-10) verify that the TcR and immunoglobulin gene families are distinct. The organization of the P-chain locus in humans is similar to that of immunoglobulin (13-17). Like immunoglobulin, the TcR /3 chain is composed of noncontiguous segments of V, J, and constant (C) region genes (13-17). Furthermore, recognition structures similar to those involved in the recombinational process in immunoglobulin are found to be adjacent to the Vp, Do, and Jo gene segments. Recently, similar findings were reported on the determination of the genomic organization of the human TcR a chain (18). In this paper, we report the genomic organization and sequences of the D, J, and C regions of the human TcR /3 chain. MATERIALS AND METHODSHuman Germ-Line Genomic Clones. The Ma...
We report the isolation and characterization of 19 classes of nonrearranging T cell-specific cDNA clones and two cDNA clones encoding the a and /3 chains of the T-cell antigen receptor from a human T-cell line, Jurkat. Results indicate that the human a-chain gene, like its /8-chain counterpart, undergoes somatic rearrangement in T cells. In addition, it shows sequence homology to its P-chain counterpart and immunoglobulin, indicating that the human a chain is also a member of the immunoglobulin supergene family. Sequence comparison suggests that the a chain also may be composed of variable (V), diversity (D), joining (J), and constant (C) region gene segments. The protein deduced from the cDNA sequence has a molecular weight of 29,995 and possesses six potential N-glycosylation sites. The availability of a-and /3-chain genes of the T-cell receptor from the same T-cell line provides tools to study their possible roles in recognition of antigens and major histocompatibility complex products by the human T-cell receptor.Antigen recognition by T lymphocytes is mediated by the T-cell antigen receptor composed of an a-and /3-chain heterodimer situated on the surface of these immunocompetent cells (1-3). About a year ago, we (4) and Hedrick et al.(5) cloned cDNAs that specified, respectively, the /3 chain of the human and mouse T-cell receptor (6). Subsequent studies have indicated that the genes encoding these structures undergo somatic rearrangement in T lymphocytes (7) and are homologous to the Ig genes (8). In addition, their genomic structures are similar, but not identical in organization, to Ig genes (9-13). These results indicate that genes encoding the T-cell receptor, at least the /8-chain gene, are different from Ig genes, though they most likely share a common ancestor (8). The finding that the human /3-chain variable (V) and constant (C) region genes (V and C) are located on chromosome 7 (14), where there are no Ig genes, confirmed that these genes are independent of Ig genes. These observations, coupled with the fact that a and ,B chains are approximately the same size, suggest that the a chain is probably also Ig-related and may contain similar V and C domains (8).In this manuscript, we report the analysis of a number of human T-cell-specific cDNA clones and describe the characterization and sequence of a human T-cell clone with homology to the a chain ofthe human T-cell antigen receptor. The results reveal that, like the /B-chain genes of the T-cell receptor (4, 5), the a-chain genes are homologous to Ig genes and undergo somatic rearrangement in T cells. While these studies were in progress, isolation of the murine a-chain cDNA (15, 16) and partial protein sequence of the human a chain (17, 18) were reported. The elucidation of the a and 83 chains of the T-cell receptor should provide the molecular tools necessary for the study of the recognition of antigens and major histocompatibility complex products by human T cells.
A cDNA clone representing the gene encoding the fi chain of the human T-cell antigen receptor has been isolated recently. By using fragments of this cDNA as hybridization probes in Southern blot analysis of restriction endonuclease-digested genomic DNA, we have now examined the structure of the gene in DNA from 26 patients with acute leukemia and from 23 normal individuals. We have found that the T-cell antigen receptor gene has undergone somatic rearrangement in 14 of 14 patients with the phenotypic diagnosis of T-cell acute lymphoblastic leukemia. In this group of patients, similar patterns of rearrangement appear to occur in different patients. This finding suggests that there is either a limited repertoire of possible rearrangements or an association between the development of leukemia and specific patterns of rearrangement. DNA from 6 patients with acute myeloblastic leukemia, 6 patients with non-B, non-T acute lymphoblastic leukemia, and 23 nonleukemic individuals showed no rearrangement or polymorphism. One case of T-cell acute lymphoblastic leukemia, however, showed rearrangement of both the T-cell receptor f3 chain and the constant region of the immunoglobulin gene. Studies with mixtures of DNAs from leukemic bone marrow cells and cultured skin fibroblasts, as well as with remission and relapse marrow DNAs from the same patients, indicate that this technique can detect 1% leukemic cells in a mixed population. In addition, DNA from the marrow of a patient in relapse contains a similar rearrangement to that found in the marrow sample taken at the time of diagnosis, which suggests that the original clone of leukemic cells was responsible for relapse. Our results indicate that assessment of rearrangement of the T-cell antigen receptor gene will be valuable in the diagnosis and management of leukemia and can be used to evaluate clonality in T-cell neoplasia.The recent isolation of cDNA clones for the mouse and human T-cell antigen receptor has made possible a number of studies regarding the ontogeny of T cells (1-3). The general genomic structure of the T-cell antigen receptor gene is similar to that of the immunoglobulin genes in that there are variable (V) regions, diversity (D), joining (J) regions, and constant (C) region elements (4, 5). Similar to immunoglobulin, the T-cell antigen receptor must be able to recognize a vast array of foreign antigens. This similarity between the immunoglobulins and the T-cell antigen receptor with regard to gene structure and protein function suggests that a similar mechanism for generating diversity of the receptor molecule is functional in both B cells and T cells.In the case of B cells, diversity is achieved in part by somatic rearrangement of the immunoglobulin genes prior to the production of a functional immunoglobulin molecule. Such rearrangements are detected by Southern blot analysis of DNA isolated from B cells. Similar rearrangements have been found in mouse and human T-cell lines when the T-cell antigen receptor gene has been used as a probe (2, 6). I...
The mammalian host defence system can be divided broadly into adaptive and non-adaptive immunity. Adaptive immunity is acquired and is mediated by B and T lymphocytes. Non-adaptive immunity is mediated in part by a small subclass of heterogeneous peripheral blood mononuclear cells. This population, termed null cells, consists of haematopoietic precursors and cells mediating natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC). NK cells are a class of non-adherent, non-phagocytic, rapidly cytotoxic lymphocytes which can efficiently lyse a wide variety of tumour cells, virally infected cells and immature cell types of normal origin. Despite the broad range of targets, only a limited number of specificities are thought to be involved in target-cell recognition. Morphologically, NK cells are large granular lymphocytes, but they have been shown to exhibit cell-surface markers characteristic of both T cells and monocytes, raising doubt over their lineage. The recent cloning of the beta-chain of the T-cell antigen receptor has now allowed us to investigate whether some NK cells are T-cell-related. We have examined rearrangement and expression of the beta-chain of the T-cell receptor in cloned murine NK cell lines and fresh murine NK cell populations, and our results support the hypothesis that a subpopulation of NK cells is related to T cells and provide basis for examining whether some NK activity is mediated by a small number of T-cell receptors.
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