Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formation of palindromic (P) region at the variable (V)-diversity (D)-joining (J) junction in DNA polymerase beta (pol-beta) deficient mice were investigated by sequencing of reverse transcriptase-polymerase chain reaction (RT-PCR) products of mRNAs encoding the beta chain of T cell receptor (TCR). Total 42 and 43 cDNA clones encoding V(beta8)-D(beta)-J(beta)-C(beta) from E18.5 embryonic thymocytes of pol-beta gene knocked-out and wild type control mouse, respectively, were sequenced. Among them five and six clones from pol-beta knocked-out and wild type, respectively, have P insertions of two nucleotides. This result unequivocally indicates that pol-beta, which is one of the repair-type DNA polymerases most abundantly expressed in thymus and spleen, is not essential for the formation of P region.
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PMID:DNA polymerase beta is not essential for the formation of palindromic (P) region of T cell receptor gene. 1147 Jan 51

T cell clones are an irreplaceable asset for the study of immune responses relevant to human pathologies. Such cells, however, cannot always be maintained in long-term culture. In order to reconstitute functional human T cell receptors (TCRs) into stable and fast growing hybridoma T cells, we developed a general approach based on a versatile cassette system, which allows cloning of all types of human T cell receptor variable alpha and beta region genes fused to murine constant regions. These chimeric constructs are easily excised and transferred into expression vectors that can be used to transfect a human CD4-expressing murine T cell hybridoma recipient. The resulting transfectants are highly stable both in terms of T cell receptor-CD3 expression and IL-2 response to the specific antigenic stimulus. Using these cassette vectors, we reconstituted the original HLA-restricted antigen specificity for two human T cell clones, one recognizing an immunodominant epitope of HIV-1 gp120, and the other recognizing an immunodominant epitope of HIV-1 reverse transcriptase. We found that the reconstituted hybridomas maintain the ability of the original T cell clones to recognize the appropriate epitope in the context of the relevant MHC either as a synthetic peptide or after processing. Their unlimited growth capacity makes them particularly suited for in vitro studies.
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PMID:Design of cassette vectors permitting cloning of all types of human TCR variable alpha and beta regions. 1147 Feb 93

PCR-based monitoring of minimal residual disease (MRD) in acute leukemias can be achieved via detection of fusion gene transcripts of chromosome aberrations or detection of immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements. We wished to assess whether both PCR targets are complementary in acute myeloid leukemia (AML). We investigated 105 consecutive AML cases for the presence of fusion gene transcripts by reverse transcriptase polymerase chain reaction (RT-PCR): AML1-ETO associated with t(8;21), CBFB-MYH11 with inv(16), PML-RARA with t(15;17), BCR-ABL with t(9;22), and MLL-AF4 with t(4;11). In 17 out of 105 AML cases (16%), fusion gene transcripts were found. Ninety-five of these AML patients (13 with fusion gene transcripts) were also investigated for the presence of IGH, IGK, TCRG and TCRD rearrangements by Southern blot and/or PCR heteroduplex analysis and sequencing. In nine out of 95 patients (9.5%), such rearrangements were found. Combined data revealed that only one patient with a fusion gene transcript had a coexistent Ig/TCR rearrangement. The nine AML patients with Ig/TCR rearrangements, as well as five additional AML patients from a previous study were investigated in more detail, revealing that Ig/TCR rearrangements in AML are immature and unusual. The presence of Ig/TCR rearrangements in AML did not correlate with RAG gene expression levels as determined by real-time quantitative PCR. In conclusion, fusion gene transcripts and Ig/TCR rearrangements are infrequent, but complementary MRD-PCR targets in AML.
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PMID:Fusion gene transcripts and Ig/TCR gene rearrangements are complementary but infrequent targets for PCR-based detection of minimal residual disease in acute myeloid leukemia. 1189 40

The mouse intestinal epithelium undergoes continuous renewal throughout life. Intraepithelial lymphocytes (IELs) represent a significant fraction of this epithelium and play an important role in intestinal mucosal barrier function. We have generated a germ-free transgenic mouse model to examine the effects of a genetically engineered proliferative abnormality in the principal epithelial cell lineage (enterocytes) on IEL census and on IEL-enterocytic cross-talk. SV40 large T antigen (TAg(Wt)) or a mutant derivative (TAg(K107/8)) that does not bind pRB was expressed in small intestinal villus enterocytes under the control of elements from the intestinal fatty acid binding protein gene (Fabpi). Quantitative immunohistochemical and flow cytometric analyses of conventionally raised and germ-free FVB/N Fabpi-TAg(Wt), Fabpi-TAg(K107/8), and nontransgenic mice disclosed that forced reentry of enterocytes into the cell cycle is accompanied by an influx of thymically educated alphabeta T cell receptor (TCR)(+) CD4(+) and alphabeta TCR(+) CD8alphabeta(+) IELs and a decrease in intestinally derived gammadelta TCR(+) CD8alphaalpha IELs. Real time quantitative reverse transcriptase-PCR studies of jejunal villus epithelium recovered from germ-free transgenic and normal mice by laser capture microdissection and gammadelta TCR(+) jejunal IELs purified by flow cytometry disclosed that the proliferative abnormality is accompanied by decreased expression of enterocytic interleukin-7 as well as IEL interleukin-7Ralpha and transforming growth factor beta3. The analysis also revealed that normal villus epithelium expresses Fms-like tyrosine kinase 3 (Flt3), a known regulator of hematopoietic stem cell proliferation and neuronal cell survival, and its ligand (Flt3L). Epithelial expression of this receptor and its ligand is reduced by the proliferative abnormality, whereas IEL expression of Flt3L remains constant. Together, these findings demonstrate that changes in the proliferative status of the intestinal epithelium affects maturation of gammadelta TCR(+) IELs and produces an influx of alphabeta TCR(+) IELs even in the absence of a microflora.
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PMID:A gnotobiotic transgenic mouse model for studying interactions between small intestinal enterocytes and intraepithelial lymphocytes. 1213 9

In Jurkat T cells, the type 3 ryanodine receptor (RyR) was knocked-down by stable integration of plasmid expressing type 3 ryanodine receptor antisense RNA. Stable integration of the antisense plasmid in individual clones was demonstrated by PCR of genomic DNA, expression of antisense RNA by reverse transcriptase PCR, and efficiently reduced expression of type 3 ryanodine receptor protein by Western blot. Selected clones were successfully used to analyze T cell receptor/CD3 complex-mediated Ca(2+) signaling. Reduced expression of the type 3 RyR resulted in (i) significantly decreased Ca(2+) signaling in the sustained phase and (ii) in permeabilized cells in a significantly impaired response toward cyclic ADP-ribose but not to d-myo-inositol 1,4,5-trisphosphate. For the first time, the role of the type 3 RyR in sustained Ca(2+) signaling was directly visualized by confocal Ca(2+) imaging as a significant contribution to the number and the magnitude of subcellular Ca(2+) signals. These data suggest that the type 3 ryanodine receptor is essential in the sustained Ca(2+) response in T cells.
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PMID:Knock-down of the type 3 ryanodine receptor impairs sustained Ca2+ signaling via the T cell receptor/CD3 complex. 1235 56

T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.
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PMID:Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders. 1247 92

To elucidate the functions of circulating gammadelta T cells, in the absence of antigen stimulation, the differential gene expression of two circulating gammadelta T cell subsets was analyzed. The two subsets, with distinct trafficking phenotypes in young calves, were GD3.5(+), CD8(-), WC1(+) or GD3.5(-), CD2(+), WC1(-), and 90-100% CD8(+) and were sorted based on GD3.5 and gammadelta T cell receptor expression. Results from two different human arrays probed with cDNA from these gammadelta T cell subsets indicated that they have markedly different tissue-specific functions. The genes preferentially expressed by GD3.5(+) (CD8(-)) gammadelta T cells demonstrated that they were highly activated, proliferative, and inflammatory, whereas those expressed by GD3.5(-) (primarily CD8(+)) gammadelta T cells were involved in promoting quiescence, consistent with a role for gammadelta T cells as sentinel mucosal cells, and several were interferon-regulated genes. Gene expression and phenotypic assays indicated that CD8(+) gammadelta T cells were apoptotic, whereas CD8(-) gammadelta T cells were apoptosis-resistant. Differential expression of multiple genes was confirmed in both arrays: That of 14 genes was confirmed by quantitative reverse transcriptase-polymerase chain reaction and that of seven proteins was confirmed by flow cytometry. This novel, genomic analysis of circulating gammadelta T cell subsets, without confounding effects of the tissue microenvironment, offers new insight into the biology and development of neonatal gammadelta T cells.
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PMID:Differential mRNA expression in circulating gammadelta T lymphocyte subsets defines unique tissue-specific functions. 1255 8

T cell dynamics and viral genotype were studied in human immunodeficiency virus 1-infected individuals receiving antiretroviral therapy who were viremic and had either increasing (discordant immunological responders) or decreasing (nonresponders) CD4(+) T cell counts. A comparison was made with treated individuals who were not viremic and had increasing CD4(+) T cell counts (complete responders). Nonresponders had higher CD4(+) T cell proliferation (as assessed by Ki67 expression) and immune activation (as assessed by CD38 and human leukocyte antigen-DR expression), together with a reduction in T cell receptor excision circles, compared with discordant immunological responders and complete responders, which suggests that there is enhanced viral pathogenicity in both peripheral T cells and the thymus. Although there was a high prevalence of mutations in the protease and reverse transcriptase genes in discordant immunological responders, these changes were also observed in nonresponders.
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PMID:Immunological and virological failure after antiretroviral therapy is associated with enhanced peripheral and thymic pathogenicity. 1279 68

The functional significance of germline transcription of T cell receptor (TCR) beta chain variable (V) region genes is under investigation. The accepted model is that transcriptional activation of germline TCR genes is associated with the rearrangement process during T-cell development. By this model, germline expression of a subset of TCR-Vbeta genes might be expected in early T cells which have not yet undergone rearrangement. Germline transcription of TCR-Vbeta genes was analysed using the reverse transcriptase (RT)-PCR in a clonal T-cell precursor line C1-V13D, a clonal pre-B cell line RAW112 and a mature T helper cell line D10.G4.1. Evidence is presented for germline transcription of TCR-Vbeta8.2 and TCR-Vbeta2.1 genes in all three cell lines, although expression in RAW112 was very weak. C1-V13D cells expressed very high levels of the whole range of transcripts including Vbeta2.1, Vbeta5.1, Vbeta5.2, Vbeta6.1, Vbeta7.1, Vbeta8.1, Vbeta8.2, Vbeta8.3 and Vbeta13.1. However, D10.G4.1 cells expressed a subset of transcripts with apparently lower levels of expression, including Vbeta2.1, Vbeta5.1, Vbeta5.2, Vbeta6.1, Vbeta8.2 and Vbeta8.3. These results raise questions about the significance and possible function of germline transcripts and/or their encoded products in early lymphoid cells and in T cells at different stages of development.
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PMID:Germline transcription of multiple TCR-Vbeta genes in cloned T-cell lines. 1528 49

Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection. Several compounds which block the attachment of HIV gp120 to either the CD4 T cell receptor or the CCR5/CXCR4 co-receptors are currently in clinical development. Most of these compounds have different molecular structures and specific mechanisms of action. These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors. For enfuvirtide, the first and, so far, only entry inhibitor approved for clinical use, the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36-45 within the HR1 region of gp41. For other entry inhibitors, multiple changes in different gp120 domains (V1, V2, V3, C2 and C4) have been associated with loss of susceptibility to these agents, although in most cases with limited cross-resistance.
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PMID:HIV entry inhibitors: mechanisms of action and resistance pathways. 1646 88


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