Adenosine DeAminase-1 (ADA-1) improves Follicular helper T cell function and vaccine response
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PROVIDER: PRJNA389585 | ENA |
REPOSITORIES: ENA
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Project description:Follicular helper T cells (Tfh) is indispensable for T-cell dependent antibody responses. Understanding the underlying mechanisms of their differentiation and function is critical for vaccine development. Using unique gene array analysis, we identified adenosine deaminase-1 (ADA-1), as a novel key molecule that drives Tfh helper program in proliferating germinal centers Tfh and circulatory Tfh cells following their interactions with B cells. ADA-1 expression and enzymatic activity is significantly higher in Tfh cells when compared to non-Tfh cells. Exogenous ADA-1 enhances the ability of less efficient cTfh and pro-follicular Tfh cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impeded Tfh function and blunted antibody response. Importantly, in vivo use of recombinant ADA-1 as an adjuvant in a DNA-based HIV vaccine enhanced Tfh differentiation and improved the quantity and the quality of HIV-specific antibody response. Thus, ADA-1 represents a good target for the design of new vaccine strategy.
2019-02-25 | GSE99781 | GEO
Project description:Follicular helper T cells (Tfh) is indispensable for T-cell dependent antibody responses. Understanding the underlying mechanisms of their differentiation and function is critical for vaccine development. Using unique gene array analysis, we identified adenosine deaminase-1 (ADA-1), as a novel key molecule that drives Tfh helper program in proliferating germinal centers Tfh and circulatory Tfh cells following their interactions with B cells. ADA-1 expression and enzymatic activity is significantly higher in Tfh cells when compared to non-Tfh cells. Exogenous ADA-1 enhances the ability of less efficient cTfh and pro-follicular Tfh cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impeded Tfh function and blunted antibody response. Importantly, in vivo use of recombinant ADA-1 as an adjuvant in a DNA-based HIV vaccine enhanced Tfh differentiation and improved the quantity and the quality of HIV-specific antibody response. Thus, ADA-1 represents a good target for the design of new vaccine strategy.
2019-02-25 | GSE99713 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-02-25 | GSE99782 | GEO
Project description:The aim of this experiment is to identify new targets of Drosophila adenosine deaminase acting on RNA (dADAR) by enriching Inosine-containing mRNA (I-mRNA) from wild type (C-S) and dADAR mutant flies and then hybridization with Drosophila cDNA arrays.
2010-06-05 | E-GEOD-529 | biostudies-arrayexpress
Project description:The aim of this experiment is to identify new targets of Drosophila adenosine deaminase acting on RNA (dADAR) by enriching Inosine-containing mRNA (I-mRNA) from wild type (C-S) and dADAR mutant flies and then hybridization with Drosophila cDNA arrays. Keywords: other
2003-07-14 | GSE529 | GEO
Project description:Gene transfer into HSCs by gammaretroviral vectors (RV) is an effective treatment for inherited blood disorders, although potentially limited by the risk of insertional mutagenesis. We evaluated the genomic impact of RV integration in T-lymphocytes from adenosine deaminase (ADA)-Severe combined immunodeficiency (SCID) patients 10 to 30 months after infusion of autologous, genetically-corrected CD34+ cells. Expression profiling on ex vivo T-cell bulk population revealed no difference with respect to healthy controls. To assess the effect of vector integration on gene expression at the single cell level, primary T-cell clones were isolated from two patients. T-cell clones harboured either one or two vector copies per cell and displayed partial to full correction of ADA expression, purine metabolism and TCR-driven functions. Analysis of retroviral integration sites (RIS) indicated a high diversity in T-cell origin, consistent with the polyclonal TCR-Vbeta repertoire. Quantitative transcript analysis of 120 genes within a 200kb-window around RIS showed modest (2.8- to 5.2-fold) disregulation of 5.8% genes in 18.6% of the T-cell clones compared to controls. Nonetheless, affected clones maintained a stable phenotype and normal functions in vitro. These results confirm that RV-mediated gene transfer for ADA-SCID is safe, and provide crucial information for the development of future gene therapy protocols. Global gene expression profiling was performed on CD4+ and CD8+ T-cell subsets purified ex vivo from three ADA-SCID patients at different times after gene therapy. The microarray analysis showed a substantial overlap with the expression patterns of T-cells from controls, indicating the absence of gross abnormalities in the development and function of T-cells derived from genetically corrected hematopoietic stem/progenitor cells. Experiment Overall Design: Transcript profiling was carried out in CD4+ and CD8+ T-cells purified with immunomagnetic beads (Miltenyi Biotec, Germany) from the peripheral blood lymphocytes of ADA-SCID patients (Pt1, 3 and 4) 10-30 months after autologous transplantation with genetically corrected CD34+ cells. At the indicated time points, the percentage of vector-positive T-cells by qPCR was >75%. Transcript profiles were determined using the Affymetrix HG-U133A microarray and compared to those of age-matched healthy controls (n=4; C1, C2, C3, C4).
2009-08-09 | E-GEOD-17354 | biostudies-arrayexpress
Project description:Follicular helper T cells (Tfh) play critical roles instructing, and initiating T-cell dependent antibody responses. The underlying mechanisms that enhance their function is therefore critical for vaccine development. Here we apply gene array analysis identifying adenosine deaminase (ADA) as a key molecule that delineates a human Tfh helper program in proliferating circulating Tfh (cTfh) cells and Germinal Centers Tfh (GC-Tfh). ADA-1 expression and enzymatic activity are increased in efficient cTfh2-17/GC-Tfh cells. Exogenous ADA-1 enhances less efficient cTfh1 and pro-follicular Tfh PD-1+ CXCR5+ cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impedes cTfh2-17/GC-Tfh function and diminished antibody response. Mechanistically, ADA-1 controls the Tfh program by influencing IL6/IL-2 production, controlling CD26 extracellular expression and could balance signals through adenosine receptors. Interestingly, dysfunctional Tfh from HIV infected-individual fail to regulate the ADA pathway. Thus, ADA-1 regulates human Tfh and represents a potential target for development of vaccine strategy.
| S-EPMC6379489 | biostudies-literature
Project description:Single-cell profiling of T lymphocytes in deficiency of adenosine deaminase 2
| PRJNA706382 | ENA
Project description:Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells
| PRJNA503859 | ENA
Project description:Cordycepin, which is an analogue of a nucleoside adenosine, exhibits a wide variety of pharmacological activities including anticancer effects. In this study, ADA1- and ADA2-expressing HEK293 cells were established to determine the major ADA isoform responsible for the deamination of cordycepin. While the metabolic rate of cordycepin deamination was similar between ADA2-expressing and Mock cells, extensive metabolism of cordycepin was observed in the ADA1-expressing cells with K m and V max values of 54.9 μmol/L and 45.8 nmole/min/mg protein. Among five natural substances tested in this study (kaempferol, quercetin, myricetin, naringenin, and naringin), naringin strongly inhibited the deamination of cordycepin with K i values of 58.8 μmol/L in mouse erythrocytes and 168.3 μmol/L in human erythrocytes. A treatment of Jurkat cells with a combination of cordycepin and naringin showed significant cytotoxicity. Our in silico study suggests that not only small molecules such as adenosine derivatives but also bulky molecules like naringin can be a potent ADA1 inhibitor for the clinical usage.
| S-EPMC4448975 | biostudies-literature