Evaluation of the expression and function of the P2X7 receptor and ART1 in human regulatory T-cell subsets
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Regulatory T cells that express CD39 (CD39%2b Treg) exhibit specific immunomodulatory properties. Ectonucleotidase CD39 hydrolyses ATP and ADP. ATP is a ligand of the P2X7 receptor and induces the shedding of CD62L and apoptosis. However, the role of ATP in CD39%2b Treg cells has not been defined. Furthermore, NAD can activate the P2X7 receptor via ADP-ribosyltransferase (ART) enzymes and cause cell depletion in murine models. We evaluated the expression and function of P2X7 and ART1 in CD39%2b Treg and CD39- Treg cells in the presence or absence of ATP and NAD. We isolated peripheral blood mononuclear cells from healthy subjects and purified CD4%2b T cells, CD4%2b CD25%2b T cells and CD4%2b CD25%2b CD39%2b T cells. P2X7 and ART1 expression was assessed by flow cytometry and real-time PCR. Our results showed low P2X7 expression on CD39%2b Treg cells and higher levels of ART1 expression in CD4%2b CD39%2b T cells than the other subtypes studied. Neither shedding of CD62L nor cell death of CD39%2b Treg or CD39- Treg cells was observed by 1mM ATP or 60. μM NAD. In contrast, P2Xs receptor-dependent proliferation with 300. μM ATP, was inhibited by NAD in the different cell types analysed. The NAD proliferation-inhibition was increased with P2Xs and A2a agonist and was reversed with P2Xs and A2a antagonist, therefore NAD inhibits P2Xs-dependent proliferation and A2a activation. In conclusion, our results suggest that the altered function and expression of P2X7 and ART1 in the human CD39%2b Treg or CD39- Treg cells could participate in the resistance against cell death induced by ATP or NAD. © 2015 Elsevier GmbH.
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ART1; ATP; CD39; Immune regulation; NAD; P2X7 receptor adenosine A2a receptor agonist; adenosine A2a receptor antagonist; adenosine triphosphate; nicotinamide adenine dinucleotide; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; purinergic P2X7 receptor; 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; 4 [2 [7 amino 2 (2 furyl) 1,2,4 triazolo[2,3 a][1,3,5]triazin 5 ylamino]ethyl]phenol; adenosine; adenosine A2 receptor; adenosine A2 receptor agonist; adenosine A2 receptor antagonist; adenosine triphosphate; apyrase; ART1 protein, human; CD39 antigen; glycosylphosphatidylinositol anchored protein; L selectin; leukocyte antigen; nicotinamide adenine dinucleotide; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; P2XR receptor, human; phenethylamine derivative; purinergic P2X7 receptor; triazine derivative; triazole derivative; animal cell; Article; CD39+ regulatory T lymphocyte; CD39- regulatory T lymphocyte; CD4+ CD25+ CD39+ T lymphocyte; CD4+ CD25+ T lymphocyte; CD4+ T lymphocyte; cell death; cell protection; controlled study; flow cytometry; human; human cell; immunomodulation; nonhuman; peripheral blood mononuclear cell; priority journal; protein expression; real time polymerase chain reaction; regulatory T lymphocyte; T cell depletion; T lymphocyte; adolescent; adult; analogs and derivatives; cell proliferation; cytology; drug effects; female; gene expression regulation; genetics; immunology; immunophenotyping; male; primary cell culture; signal transduction; T lymphocyte subpopulation; Adenosine; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Adenosine Triphosphate; Adolescent; ADP Ribose Transferases; Adult; Antigens, CD; Apyrase; Cell Death; Cell Proliferation; Female; Gene Expression Regulation; GPI-Linked Proteins; Humans; Immunophenotyping; L-Selectin; Male; NAD; Phenethylamines; Primary Cell Culture; Receptors, Adenosine A2; Receptors, Purinergic P2X7; Signal Transduction; T-Lymphocyte Subsets; Triazines; Triazoles
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