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Results for “Genes, T-Cell Receptor alpha”

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At least 19 recordsLinked to original sources
PubMed1992

CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen.

Molecules encoded by the human CD1 locus on chromosome 1 (ref. 33) are recognized by selected CD4-8- T-cell clones expressing either alpha beta or gamma delta T-cell antigen receptors. The known structural resemblance of CD1 molecules to antigen-presenting molecules encoded by major histocompatibility complex (MHC) genes on human chromosome 6 (refs 3, 4, 34, 35), suggested that CD1 may represent a family of antigen-presenting molecules separate from those encoded in the MHC. Here we report that the proliferative and cytotoxic responses of human CD4-8- alpha beta TCR+ T cells specific for Mycobacterium tuberculosis can be restricted by CD1b, one of the four identified protein products of the CD1 locus. The responses of these T cells to M. tuberculosis seemed not to involve MHC encoded molecules, but were absolutely dependent on the expression of CD1b by the antigen-presenting cell and involved an antigen processing requirement similar to that seen in MHC class II-restricted antigen presentation. These results provide, to our knowledge, the first direct evidence for the proposed antigen-presenting function of CD1 molecules and suggest that the CD1 family plays a role in cell-mediated immunity to microbial pathogens.

Antigen-Presenting Cells↗
PubMed2025

Comparative Analysis of Mammalian Adaptive Immune Loci Revealed Spectacular Divergence and Common Genetic Patterns.

Adaptive immune responses are mediated by the production of adaptive immune receptors, antibodies, and T-cell receptors, which bind antigens, thus causing their neutralization. Unlike other proteins, adaptive immune receptors are not fully encoded in the germline genome and result from a complex of somatic processes collectively called V(D)J recombination affecting germline immunoglobulin (IG) and T-cell receptor (TR) loci consisting of template genes. While various existing studies report extreme diversity of antibodies and T-cell receptors, little is known about the diversity of germline IG and TR loci. To overcome this gap, the first comparative analysis of full-length sequences of IG/TR loci across 46 mammalian species from 13 taxonomic orders was performed. First, germline gene counts were shown to correlate in immunoglobulin heavy chain immunoglobulin heavy chain (IGH)/immunoglobulin lambda (IGL) loci and T-cell receptor alpha (TRA)/T-cell receptor beta (TRB) and anticorrelate in immunoglobulin kappa (IGK)/IGL, possibly indicating coevolution between corresponding chains. Second, structures of IG/TR loci were analyzed, and it was shown that IG/TR loci formed by long arrays of high multiplicity repeats are more common for species that have experienced population bottlenecks. Finally, haplotypes of IG/TR loci with little or no sequence similarity within a species were found, suggesting that they may have a limited potential for homologous recombination. These results demonstrate that IG/TR loci are rapidly evolving genomic regions whose structural variation is shaped by the population history of the species and open new perspectives for immunogenomics studies.

Animals↗
PubMed1992

Molecular analysis of a new translocation, t(X;14)(q28;q11), in premalignancy and in leukaemia associated with ataxia telangiectasia.

The disease ataxia telangiectasia (A-T) is a multifaceted disorder in which patients have an increased chance of developing a T-cell leukaemia, often with abnormalities of chromosome 14, but sometimes with rare translocations, like t(X;14)(q28;q11). We describe the cloning of the breakpoint of one such novel t(X;14) from an A-T patient. The translocation breaks within the T cell receptor alpha chain gene on chromosome 14 at band q11 and in a region of the X chromosome, within about 1 Mb of the telomere of the long arm. The patient subsequently developed T-cell prolymphocytic leukaemia (T-PLL), and molecular examination showed that the tumour cells carried the same t(X;14) breakpoint as that cloned from the premalignant cells. The same breakpoint could be detected in blood samples taken as much as 5 years prior to diagnosis of T-PLL. This suggests a role for the abnormality in the tumour development in this patient but implies that other mutational events were necessary for overt disease to become manifest.

Adult↗
PubMed1992

Sequence diversity of T cell receptor alpha chain transcripts from BALB/c thymus.

Most of the diversity in T cell receptor subunits resides in the region that is the equivalent of the CDR3 of immunoglobulins. In order to learn more about the relative contributions of the various mechanisms that generate this diversity we have analyzed the sequences of alpha chain transcripts from BALB/c thymus. The J alpha repertoire of BALB/c mice was examined by comparison of new J alpha sequences and previously published sequences. Among the 41 J alpha genes examined, most of the diversity is located at the 5' end, consistent with the notion that this region contacts the antigen. VJ junctional diversity was examined by sequencing various V alpha J alpha combinations derived from different stages of development. Deletion of bases from the ends of V and J genes does not occur with equal frequency. A greater number of bases were deleted on average from the ends of J genes. Bases were added at junctions frequently in isolates from adult animals, consistent with the presence of terminal deoxynucleotidyl transferase. However, there were short stretches of sequences at junctions which were also present at the 5' end of J genes. These findings extend recent observations that alpha chain genes use multiple mechanisms for generating diversity.

Aging↗
PubMed1992

Activation of human peripheral blood T lymphocytes by pharmacological induction of protein-tyrosine phosphorylation.

Protein-tyrosine kinase and protein-tyrosine phosphatase (PTPase) activities are essential for T-cell antigen receptor-mediated signaling. To assess the functional consequences of alteration of the levels of tyrosine phosphorylation in normal human T cells, the effects of vanadate and hydrogen peroxide were studied. In combination, these agents induced tyrosine phosphorylation of cellular substrates, elevated cytosolic free calcium, and induced interleukin 2 receptor (IL-2R) alpha chain expression but not IL-2 secretion. However, anti-CD28 antibody in combination with vanadate and hydrogen peroxide induced IL-2 secretion, consistent with the requirement for a costimulatory signal in the induction of this gene. The effects of vanadate and hydrogen peroxide were enhanced in the absence of the T-cell PTPase, CD45. Thus, acute pharmacologic manipulation of the level of tyrosine phosphorylation in normal T cells correlates with partial, but not full, activation of these cells; in concert with a costimulatory signal provided by perturbation of the CD28 molecule, the complete program of activation is initiated. These agents should prove useful in dissecting signaling pathways involved in the regulation of genes critical to the immune response.

Animals↗
PubMed2013

MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation.

Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTLs, and that deletion or depletion of Dicer in mouse or human activated CD8(+) T cells causes up-regulation of perforin, granzymes, and effector cytokines. Genome-wide analysis of microRNA (miR, miRNA) changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of an miRNA network that controls perforin, eomesodermin, and IL-2Rα expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation, and antigenic stimulation. Overall, our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation.

Adoptive Transfer↗
PubMed2026

Multi-omics-based study on the biological characteristics of kidney renal deficiency and blood stasis in ankylosing spondylitis.

OBJECIVE: To explore the objective biological evidence for the classification and diagnosis of Traditional Chinese Medicine (TCM) syndromes in ankylosing spondylitis (AS) using multiomics analysis. METHODS: Patients with AS were categorized into kidney deficiency and blood stasis syndrome (SX group) and damp-heat stasis syndrome (SR group). Transcriptomic sequencing and quantitative plasma proteomics were performed on patients with AS and healthy volunteers. Multiomics integration was used to characterize the biological basis of AS with renal deficiency and blood stasis syndrome. Specific proteins were validated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Transcriptomic sequencing identified 31 significantly upregulated genes in patients with AS compared to healthy controls. These genes were primarily involved in tumor necrosis factor, interleukin-17, and nuclear factor kappa-B signaling pathways, as well as osteoblast differentiation and various viral infection pathways. Differentially expressed genes, including intercellular adhesion molecule 1 (ICAM1), 6-phosphofructo-2-kinase, cyclin-dependent kinase inhibitor 1A, interleukin 1 receptor antagonist, integrin alpha IIb, and myosin light chain 9 were more upregulated in the SX group than in the SR group. Quantitative proteomics identified 723 differential proteins associated with the disease and 788 differential proteins between the SX and SR groups. Notable proteins such as myeloperoxidase, cluster of differentiation 14, macrophage simulating 1 (MST1), and Ras homolog enriched in brain may serve as characteristic proteins of the SX group. By integrating transcriptomic and proteomic data, 45 associated differential molecules involved in platelet activation, pathogenic intestinal flora infection, glycolysis/gluconeogenesis, and T-cell receptor signaling pathways were identified in patients with AS compared to healthy controls. Additionally, ICAM1, MST1, C-X-C motif chemokine ligand 8 (CXCL8), suppressor of cytokine signaling 3 (SOCS3), and insulin-like growth factor binding protein 1 (IGFBP1) were detected in TCM syndromes by RT-qPCR and ELISA, showing upregulation in AS renal deficiency and blood stasis syndromes, which is consistent with the proteomic and transcriptomic results. CONCLUSIONS: ICAM1, MST1, CXCL8, SOCS3, and IGFBP1 were identified as biomarkers of renal deficiency and blood stasis syndrome in AS. This study provides a biological basis for the differential diagnosis of TCM syndromes in AS, offering new insights into Chinese medicine evidence and more precise Chinese medicine treatments for AS.

Humans↗
PubMed1992

T-cell receptor beta usage by 35 different antigen-specific T-cell clones restricted by HLA-Dw4 or -Dw14.1.

We studied whether antigen-specific T cells being restricted by the very similar HLA-Dw4 and/or -Dw14.1 molecules might demonstrate homogeneities in parts of their TCR. TCCs were generated from three individuals who were all HLA-Dw4/Dw14.1 heterozygous. Thirty-five TCCs specific for PPD or TT and restricted by HLA-Dw4 and/or -Dw14.1 were selected for TCR beta gene sequencing. We found that 19 different V beta genes from 13 V beta families were expressed by these TCCs. Thus, it seems that many different TCRV beta genes may be used by TCCs restricted by these HLA molecules. For PPD-specific TCCs, a possible biased usage of V beta 8, as well as possible preferential usage of a CDR3 motif, were found.

Amino Acid Sequence↗
PubMed1992

The dual role of the cAMP-dependent protein kinase C alpha subunit in T-cell receptor-triggered T-lymphocytes effector functions.

In order to directly evaluate the role of the cAMP-dependent protein kinase (PKA) catalytic (C) subunit in T-cell receptor- (TCR) triggered cytotoxic T-lymphocytes (CTL) effector functions, cells were studied after pretreatment with antisense oligomers complementary to mRNA for the C alpha or C beta subunits. C alpha subunit is shown to be predominantly expressed in CTL. In some experiments the pretreatment of the CTL with the C alpha antisense, but not with the control or C beta antisense oligomers, resulted in the inhibition of cAMP-independent PKA activity without significantly affecting the level of total cAMP-inducible PKA activity. In parallel assays, CTL which were pretreated with the C alpha antisense oligomer had enhanced antigen-bearing target cell-triggered-, anti-TCR monoclonal antibody-triggered-, and phorbol 12-myristate 13-acetate/A23187-triggered exocytosis of granules, as well as enhanced antigen-specific cytotoxicity. In contrast, the TCR-triggered gamma-interferon mRNA expression and gamma-interferon secretion were inhibited in C alpha antisense-pretreated CTL. These results suggest that the C alpha subunit of PKA may have a dual role in regulation of T-lymphocytes effector functions: (i) it may down-regulate TCR-triggered protein-synthesis independent responses such as cytotoxicity and exocytosis, thereby counteracting TCR-triggered activation even in the absence of the second messenger, cAMP, and (ii) the C alpha subunit activity is likely to be required for the nuclear and/or cytoplasmic events in CTL's activation involved in lymphokine synthesis and secretion.

Animals↗
PubMed1992

Rhom-2 expression does not always correlate with abnormalities on chromosome 11 at band p13 in T-cell acute lymphoblastic leukemia.

A frequent site for nonrandom recombination in T-cell acute lymphoblastic leukemia (T-ALL) is chromosome 11 at p13. The molecular characterization of a (7;11)(q35;p13) translocation showed that the translocation breakpoint was 2 kb 5' to the T-ALLbcr locus resulting in the juxtaposition of the T-cell receptor (TCR) beta gene to the rhom-2 gene locus. Northern blot analysis did not detect expression of the rhom-2 gene in the leukemic blasts of the (7;11) translocation. However, using a sensitive polymerase chain reaction (PCR)-based assay, the (7;11) translocation showed a trace expression of rhom-2 at a level of 0.01% of TCR-beta message. Because rhom-2 is considered a proto-oncogene, the significance of the trace expression of rhom-2 in the (7;11) translocation was investigated by comparing the level of rhom-2 expression in 7 additional T-ALLs, normal thymocytes, and CEM (pre-T) and HPB (mature-T) cell lines using the PCR assay. The CEM cells, normal thymocytes, and one patient, whose blasts had no cytogenetic abnormality of chromosome 11, did not express rhom-2 indicating that rhom-2 is not normally expressed in T cells. The other six T-ALLs fell into three categories: (1) two T-ALLs overexpressed rhom-2 in the presence of a translocation; (2) two T-ALLs had trace expression in the presence of a translocation; and (3) two T-ALLs had trace expression with no observable abnormalities on chromosome 11 at p13. Therefore, the data indicate that not all translocations at the T-ALLbcr locus result in overexpression of rhom-2. To account for the sharp contrast in rhom-2 expression seen in these T-ALLs, a model is proposed with a negative regulatory element in the T-ALLbcr locus that is disrupted in some of the cases leading to overexpression of rhom-2.

Base Sequence↗
PubMed1992

Multiple sclerosis: an autoimmune disease of multifactorial etiology.

The etiology of multiple sclerosis is linked to a variety of genetic and environmental factors. Both cell-mediated and humoral immune responses, triggered by extraneous or autoantigens, are likely to contribute to the pathogenesis of this disease. A greater insight into the fundamental cause of multiple sclerosis has been provided by the recognition that certain immune response genes are associated with an increased susceptibility to the disease. Such knowledge should provide new opportunities for selective therapeutic interventions.

Animals↗
PubMed2026

Directing fratricide within T cell products using an anti-uPAR chimeric antigen receptor to drive the production of potent therapeutic cells.

Cell therapy manufacturing of primary T cells often results in heterogeneous cell populations in the final product, with many cells lacking desired receptor expression or exhausted and other dysfunctional phenotypes. Here, we design a novel cell-intrinsic strategy to genetically reprogram primary human T cells to autonomously detect and eliminate dysfunctional cells. This integrated detection and elimination process, known as directed fratricide, is programmed via non-viral CRISPR genome editing to eliminate the T cell receptor (TCR) alpha chain (TRAC gene knockout) and integrate a chimeric antigen receptor (CAR) against the urokinase-type plasminogen activator receptor (uPAR), also known as CD87. In these cell products, strong T cell stimulation or activation during manufacturing causes a small subset of cells to express uPAR, which triggers CAR-mediated killing within the product. This fratricide induces proliferation in the desired cells and destroys undesired cells, a process that could be modeled computationally and controlled robustly via supplements to the culture media. The strategy enabled enrichment of anti-uPAR and anti-disialoganglioside (GD2) CAR-T cell products up to ≥99% CAR+/TCR-, favoring a memory-like phenotype. Understanding growth dynamics among T cell subsets and reprogramming them via CRISPR could accelerate the biomanufacturing of potent cell products without extensive selection methods.

Humans↗
PubMed1992

Calcineurin mediates inhibition by FK506 and cyclosporin of recovery from alpha-factor arrest in yeast.

The structurally unrelated immunosuppressants FK506 and cyclosporin A (CsA) act similarly, inhibiting a Ca(2+)-dependent signal required for interleukin-2 transcription and T-cell activation. Each drug binds to its cytosolic receptor, FKBP-12 and cyclophilin, respectively, and the drug-receptor complexes inhibit the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. In yeast, calcineurin has been implicated in recovery from alpha-mating factor arrest. Here we show that FK506 bound to yeast FKBP-12 appears to form a complex with yeast calcineurin. Moreover, recovery from mating factor arrest is highly sensitive to FK506 or CsA, and this sensitivity requires the presence of FKBP-12 or cyclophilin, respectively. These results define a key physiological target of an FK506- and CsA-sensitive signal pathway in yeast, suggest a high degree of mechanistic conservation with mammalian cells, and indicate that further examination of the yeast system should provide insight into the same process in T cells.

Alleles↗
PubMed1992

Generation of monoclonal antibodies against a human T cell receptor beta chain expressed in transgenic mice.

The generation of a panel of monoclonal antibodies specific for different variable (V) regions of human T cell receptors will be of great importance in the study of T cell-mediated diseases. However, relatively few such reagents exist, due in part to the poor immunogenicity of TcRs on the surface of human T cells. We have employed a strategy in which T cells from a transgenic mouse line expressing a human V beta 3 C beta 1 TcR were used to immunise syngeneic conventional mice to generate two monoclonal antibodies specific for human T cell receptors. Binding of antibody JOVI.3, which stained approximately 5% of human peripheral blood CD3 positive T cells, correlated with the expression of the human TcR V beta 3 gene segment. Antibody JOVI.1 recognised a determinant on the majority of TcRs, staining 50-75% of peripheral blood T cells and T cell lines expressing different V beta regions. Some TcRs, however, failed to react with this antibody. Both antibodies immunoprecipitated detergent-solubilised TcR molecules and were capable of inducing proliferation of peripheral blood T cells.

Animals↗
PubMed1992

Hand mirror variant of adult acute lymphoblastic leukemia. Evidence for a mixed leukemia.

Blast cells from a female patient with acute lymphoblastic leukemia-hand mirror variant were examined using various techniques, including light and ultrastructural morphologic examination, cytochemical analysis, surface antigen characterization, cytogenetic analysis, and gene rearrangement studies. The blast cells were found to be pre-B cells (CD19+ and Tdt+) that also expressed the myeloid antigens CD13 and CD33 and demonstrated a heavy chain immunoglobulin gene rearrangement. Cytogenetic studies revealed a t(11;19) translocation previously described in biphenotypic leukemias. A subset of acute lymphoblastic leukemia-hand mirror cells has been previously defined and includes predominately female patients with an indolent course. The authors' findings place this case, a mixed leukemia, within that subgroup. The possibility of mixed lineage should be considered in future cases of hand mirror variants of adult acute lymphoblastic leukemia. Furthermore, hand mirror morphologic features in any case of acute leukemia should alert the hematopathologist/hematologist to the possibility of mixed lineage.

Adult↗
PubMed2026

BHLHE40 and ChREBP associate with hepatic enhancer clusters containing PPARα, RXRα, and HNF4 nuclear receptors.

BHLHE40/DEC1 is a basic helix-loop-helix transcription factor (TF) that regulates circadian rhythm and T-cell responses. In hepatocytes, its function and interplay with other TFs are poorly understood. Employing a genome-wide approach, we show that its genomic binding strongly overlapped with that of carbohydrate response-element binding protein, a sugar-sensing TF and known inducer of BHLHE40 expression. Transcriptomic analysis of primary mouse hepatocytes revealed reduced expression of genes involved in genomic stability on Bhlhe40 knockdown by siRNA. Bhlhe40 depletion potentiated fructose responsiveness of genes involved in cell-cycle regulation. Strikingly, genomic binding of BHLHE40 extensively overlapped with enhancers occupied by PPARα, RXRα, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPARα target genes. Using HEK293 cells, we further observed that BHLHE40 physically interacted with RXRα and PPARα cofactors. Collectively, our data suggest that through cooperation with carbohydrate response-element binding protein and nuclear receptors, BHLHE40 is a central regulator of hepatic gene expression with potential to integrate inputs from nutrient signals contributing to the metabolic flexibility of the liver.

Animals↗
PubMed1992

Human CD8+ T cell clone regulates autologous CD4+ myelin basic protein specific T cells.

Normal human CD8+ T cell clones were co-isolated from the same culture wells as CD4+ T effector cell clones specific for myelin basic protein (MBP). Microcultures from which the CD8+ clones were isolated initially proliferated weakly to whole MBP and to an MBP peptide spanning residues 90-170. This pattern of response was similar to strongly proliferating wells that yielded CD4+ T cell clones specific for the 90-170 peptide. After repeated stimulation, however, no response to MBP or MBP 90-170 was detected, even though the number of cells increased after stimulation. Phenotyping and TCR analyses revealed the presence of two CD8+, CD4-, IL-2R+ T cell isolates that expressed a single V beta gene (V beta 17) that differed from the CD4+ isolates that uniformly expressed V beta 14. One of these CD8+ clones (C9) inhibited the antigen-driven proliferation of an autologous MBP 90-170 reactive clone but not an autologous clone specific for Herpes simplex virus (HSV), without affecting MHC non-restricted mitogen responses of the same clones. Moreover, C9 did not inhibit heterologous CD4+ T cell clones specific for MBP 1-38 or 90-170. A culture supernatant of the CD8+ clone showed the same pattern but lower levels of inhibition. C9 had mild cytolytic activity when incubated at high ratios with an autologous MBP-specific CD4+ clone. Lysis was blocked completely by anti-MHC class I antibodies, but not by anti-MHC II antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Expression of surface lymphotoxin and tumor necrosis factor on activated T, B, and natural killer cells.

The expression of membrane-associated forms of lymphotoxin (LT) and TNF were examined on cell lines of T, B, and myeloid origin, IL-2 dependent T cell clones, and peripheral blood lymphocytes. Inducible and constitutive patterns of surface LT expression were found on T cells as exemplified by the II-23.D7, a CD4+T cell hybridoma, and HUT-78, a T cell lymphoma. Phorbol ester induced surface LT expression on Ramos, an EBV transformed B cell line, but at a slower rate of appearance when compared to the II-23.D7. Secretion of LT was rapidly inducible by phorbol ester in II-23.D7 and also in HUT-78 but with slower kinetics; surface LT expression continued in both lines after secretion had ceased. Low levels of membrane TNF were transiently induced on II-23.D7 and HUT-78, but none was observed on Ramos. Peripheral blood monocytes and some myeloid tumor lines did not express surface LT. Several T cell clones expressed surface LT after Ag-specific stimulation, and expression persisted several days. Stimulation through the TCR or by IL-2 rapidly induced surface LT on resting peripheral T cells and CD56+ NK cells; pokeweed mitogen activation induced expression on CD20+ B cells. Consistent with previous results, immunoprecipitation with anti-LT mAb showed that LT was complexed with a distinct 33 kDa glycoprotein (p33) on cells that expressed surface LT, whereas secreted LT was not associated with p33. Surface and secreted modes of LT expression by activated T, B, and NK cells suggests that LT can be utilized as either a localized or diffusible mediator in immune responses.

Antigens, CD↗