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Blood, 1 January 2008, Vol. 111, No. 1, pp. 251-259. Prepublished online as a Blood First Edition Paper on October 1, 2007; DOI 10.1182/blood-2007-03-081646. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-03-081646v1 111/1/251    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zarek, P. E Articles by Powell, J. D Search for Related Content PubMed PubMed Citation Articles by Zarek, P. E Articles by Powell, J. D Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 26, 2007 Accepted September 25, 2007 A2A receptor signaling promotes peripheral tolerance by inducing T cell anergy and the generation of adaptive regulatory T cells Paul E Zarek, Ching-Tai Huang, Eric R Lutz, Jeanne Kowalski, Maureen R Horton, Joel Linden, Charles G Drake, and Jonathan D Powell* Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States Department of Oncology Biostatistics, Johns Hopkins University School of Medicine, Baltimore, MD, United States Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States Department of Medicine, Unviersity of Virginia, Charlottesville, VA, United States * Corresponding author; email: poweljo{at}jhmi.edu. Tissue-derived adenosine, acting via the adenosine A2A receptor (A2AR), is emerging as an important negative regulator of T cell function. In this report we demonstrate that A2AR stimulation not only inhibits the generation adaptive effector T cells, but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A2AR engagement induces T cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A2AR agonist fail to proliferate and produce IL-2 and IFN- when rechallenged in the absence of A2AR stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A2AR stimulation inhibits IL-6 expression while enhancing the production of TGF-. Accordingly, treating mice with A2AR agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3+ and LAG-3+ regulatory T cells. In this regard, A2AR agonists fail to prevent autoimmunity by LAG-3-/- clonotypic T cells implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A2AR to promote long-term T cell anergy and the generation of adaptive regulatory T cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Ohta, A. Ohta, M. Madasu, R. Kini, M. Subramanian, N. Goel, and M. Sitkovsky A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments J. Immunol., November 1, 2009; 183(9): 5487 - 5493. [Abstract] [Full Text] [PDF] M. Mandapathil, M. J. Szczepanski, M. Szajnik, J. Ren, D. E. Lenzner, E. K. Jackson, E. Gorelik, S. Lang, J. T. Johnson, and T. L. Whiteside Increased Ectonucleotidase Expression and Activity in Regulatory T Cells of Patients with Head and Neck Cancer Clin. Cancer Res., October 15, 2009; 15(20): 6348 - 6357. [Abstract] [Full Text] [PDF] C. L. Lau, Y. Zhao, I. L. Kron, M. H. Stoler, V. E. Laubach, G. Ailawadi, and J. Linden The Role of Adenosine A(2A) Receptor Signaling in Bronchiolitis Obliterans. Ann. Thorac. Surg., October 1, 2009; 88(4): 1071 - 1078. [Abstract] [Full Text] [PDF] A. D. Wells New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting J. Immunol., June 15, 2009; 182(12): 7331 - 7341. [Abstract] [Full Text] [PDF] J. M. Wilson, W. G. Ross, O. N. Agbai, R. Frazier, R. A. Figler, J. Rieger, J. Linden, and P. B. Ernst The A2B Adenosine Receptor Impairs the Maturation and Immunogenicity of Dendritic Cells J. Immunol., April 15, 2009; 182(8): 4616 - 4623. [Abstract] [Full Text] [PDF] B. Csoka, L. Himer, Z. Selmeczy, E. S. Vizi, P. Pacher, C. Ledent, E. A. Deitch, Z. Spolarics, Z. H. Nemeth, and G. Hasko Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function FASEB J, October 1, 2008; 22(10): 3491 - 3499. [Abstract] [Full Text] [PDF] U. Schenk, A. M. Westendorf, E. Radaelli, A. Casati, M. Ferro, M. Fumagalli, C. Verderio, J. Buer, E. Scanziani, and F. Grassi Purinergic Control of T Cell Activation by ATP Released Through Pannexin-1 Hemichannels Sci. Signal., September 30, 2008; 1(39): ra6 - ra6. [Abstract] [Full Text] [PDF]

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