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Blood, 15 January 2008, Vol. 111, No. 2, pp. 964-965. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gorini, S. Articles by la Sala, A. Search for Related Content PubMed PubMed Citation Articles by Gorini, S. Articles by la Sala, A. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE Hydrolysis of extracellular ATP and immune suppression: humans versus mice To the editor: We read with interest the recent article by Borsellino and colleagues on the role of CD39 and CD73 for the suppressor activity of Foxp3+ regulatory T cells (T regs).1 Because the major sources of extracellular ATP are injured cells leaking cytoplasmic content, degranulating platelets, and endothelial cells under shear stress, extracellular ATP may represent a constitutive endogenous molecule that signals tissue stress and injury. Borsellino and colleagues proposed that the immune suppressive activity of T regs is due, at least in part, to their capacity to remove ATP from the extracellular space through the enzymatic activity of CD39 and CD73 expressed on their membrane. It has been recently shown that T regs exert immune suppression by elevating intracellular cyclic AMP (cAMP) concentration in target cells.2 As suggested by Borsellino and others, T regs might do so by degrading ATP to adenosine. In turn, adenosine activates adenylyl cyclases by triggering the cognate Gs-protein coupled receptor A2a.1,3 However we would like to point out that in human cells ATP can act as a direct cAMP-elevating agent thus delivering a potent anti-inflammatory signal. This is because human, but not murine, cells express the purinergic receptor P2Y11 that is the only P2 purinergic receptor coupled to adenylyl cyclases activation.4 Cells expressing P2Y11 include dendritic cells (DCs), macrophages, T lymphocytes, and natural killer cells. Human DCs- exposed to micromolar concentrations of extracellular ATP do not undergo "classic" maturation. In fact, although ATP-stimulated DCs up-regulate costimulatory membrane molecules, they also display blocked pro-inflammatory cytokine and chemokine production including tumor necrosis factor- (TNF-), interleukin-1 (IL-1), IL-12, CCL2, CCL3, CCL5, and CXCL10, while IL-10 and IL1Ra are either unaffected or up-regulated.5–7 Moreover, extracellular ATP induces DCs to produce large amounts of Thrombospondin-1 and synergyzes with interferon- (IFN-) in up-regulating indoleamine 2,3 dioxygenase, turning DCs into tolerogenic antigen presenting cells.8 These effects are mimicked by the nonhydrolyzable ATP analog ATP--S and by several cyclic AMP elevating agents, as well as by the administration of cell permeable cAMP analogs.8,9 Moreover, extracellular ATP has proven able to inhibit T lymphocyte and NK cell proliferation and cytokine production as well as NK-mediated cytotoxicity, associated with increased intracellular cAMP concentration.10 Extracellular ATP released from injured cells might not act as an activating danger signal but it might rather represent a negative feedback for immune cells to limit self-harmful excessive inflammation in the context of extensively damaged human tissues. This view suggests that extracellular ATP hydrolysis operated by human CD39+ T regs might have more complex physiologic consequences than blunt immune suppression. Authorship Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Andrea la Sala, Laboratory of Molecular and Cellular Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Via dei Bonacolsi, 81, 00163 Rome, Italy; e-mail: andrea.lasala{at}sanraffaele.it. Stefania Gorini, and Andrea la Sala References Borsellino G, Kleinewietfeld M, Di Mitri D, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007; 110:1225–1232.[Abstract/Free Full Text] Bopp T, Becker C, Klein M, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007; 204:1303–1310.[Abstract/Free Full Text] Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257–1265.[Abstract/Free Full Text] Abbracchio MP, Burnstock G, Boeynaems JM, et al. International Union of Pharmacology LVIII: Update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 2006; 58:281–341.[Abstract/Free Full Text] la Sala A, Ferrari D, Corinti S, et al. Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses. J Immunol 2001; 166:1611–1617.[Abstract/Free Full Text] la Sala A, Sebastiani S, Ferrari D, et al. Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes. Blood 2002; 99:1715–1722.[Abstract/Free Full Text] Horckmans M, Marcet B, Marteau F, et al. Extracellular adenine nucleotides inhibit the release of major monocyte recruiters by human monocyte-derived dendritic cells. FEBS Lett 2006; 580:747–754.[CrossRef][Medline] [Order article via Infotrieve] Marteau F, Gonzalez NS, Communi D, et al. Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells. Blood 2005; 106:3860–3866.[Abstract/Free Full Text] Ferrari D, Gorini S, Callegari G, la Sala A. Shaping immune responses through the activation of dendritic cells' P2 receptors. Purinergic Signal 2007; 3:99–107.[CrossRef][Medline] [Order article via Infotrieve] Miller JS, Cervenka T, Lund J, Okazaki IJ, Moss J. Purine metabolites suppress proliferation of human NK cells through a lineage-specific purine receptor. J Immunol 1999; 162:7376–7382.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Hydrolysis of extracellular ATP by CD39+ Treg cells: context matters! Markus Kleinewietfeld, Diletta DiMitri, Alexander Sternjak, Adamo Diamantini, Giovanna Borsellino, Luca Battistini, Olaf Rötzschke, and Kirsten Falk Blood 2008 111: 965-966. [Full Text] [PDF] Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression Giovanna Borsellino, Markus Kleinewietfeld, Diletta Di Mitri, Alexander Sternjak, Adamo Diamantini, Raffaella Giometto, Sabine Höpner, Diego Centonze, Giorgio Bernardi, Maria Luisa Dell'Acqua, Paolo Maria Rossini, Luca Battistini, Olaf Rötzschke, and Kirsten Falk Blood 2007 110: 1225-1232. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gorini, S. Articles by la Sala, A. Search for Related Content PubMed PubMed Citation Articles by Gorini, S. Articles by la Sala, A. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

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