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Monophosphate and Phosphatases ′,5 Adenosine Acts through A2 Receptors to Inhibit IL-2-Induced Tyrosine Phosphorylation of STAT5 in T Lymphocytes: Role of Cyclic Adenosine 3 ′,5′ This information is current as -Monophosphate and Phosphatases of September 28, 2021. Hong Zhang, David M. Conrad, Jared J. Butler, Chuanli Zhao, Jonathan Blay and David W. Hoskin J Immunol 2004; 173:932-944; ; doi: 10.4049/jimmunol.173.2.932 Downloaded from http://www.jimmunol.org/content/173/2/932 References This article cites 70 articles, 35 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/173/2/932.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Adenosine Acts through A2 Receptors to Inhibit IL-2-Induced Tyrosine Phosphorylation of STAT5 in T Lymphocytes: Role of Cyclic Adenosine 3؅,5؅-Monophosphate and Phosphatases1 Hong Zhang,* David M. Conrad,* Jared J. Butler,* Chuanli Zhao,* Jonathan Blay,† and David W. Hoskin2*‡ Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A1,A2a,A2b,A3)on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. Downloaded from The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain- containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A2 receptor agonists and was blocked by selective A2a and A2b receptor antagonists, indicating that adenosine was mediating its effect through A2 receptors. Inhibition of STAT5a/b phosphorylation was http://www.jimmunol.org/ reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/ protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A2 receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells. The Journal of Immunology, 2004, 173: 932–944. denosine is a purine nucleoside that interacts with cell mune responses because comparable concentrations of adenosine surface receptors to mediate both anti-inflammatory and suppress the activation of T lymphocytes to a killer phenotype by guest on September 28, 2021 A immunosuppressive activities (1, 2). In addition to at- (11), as well as the recognition/adhesion and effector phases of tenuating neutrophil and macrophage function (3, 4), adenosine is tumor cell destruction by cytotoxic lymphocytes (12–14). The in- a potent inhibitor of T cell-mediated immune responses (5, 6). In hibitory effects of adenosine on the induction and effector function this regard, adenosine may be an important mediator of tumor- of tumoricidal T lymphocytes may be the result of adenosine-in- associated immune suppression. Solid tumors contain local regions duced alterations in T cell signaling pathways. In this regard, aden- of hypoxia (7), which are associated with increased adenosine pro- osine has been shown to inhibit TCR triggering (6, 13) and the duction and release through adenosine kinase inhibition and ade- activity of the protein tyrosine kinase 56lck (15), which is an im- Ј nine nucleotide breakdown via the 5 -nucleotidase pathway (8, 9). portant initiator of the TCR signaling cascade (16). However, the ϳ ␮ Moreover, the level of adenosine ( 10 M) that is present in the effect of adenosine on IL-2R-associated signaling pathways has extracellular fluid of mouse and human carcinomas grown in im- not yet been explored in T lymphocytes. mune-deficient mice is more than sufficient to suppress T cell func- IL-2 is an immunomodulatory cytokine that is essential for the tion (10). Elevated concentrations of adenosine within the tumor growth and survival of activated T lymphocytes (17). The IL-2R microenvironment may interfere with cell-mediated antitumor im- consists of three subunits designated ␣, ␤, and ␥ (18). An IL-2R␤ chain combines with an IL-2R␥ chain to yield an intermediate ␣ Departments of *Microbiology and Immunology, †Pharmacology, and ‡Pathology, affinity IL-2R, whereas the addition of an IL-2R chain results in Dalhousie University, Halifax, Nova Scotia, Canada the formation of a high affinity IL-2R. IL-2R signaling intermedi- Received for publication April 11, 2003. Accepted for publication May 5, 2004. ates involved in the transduction of a proliferative signal include The costs of publication of this article were defrayed in part by the payment of page Jak1, Jak3, and STAT5 (19, 20). The tyrosine kinases Jak1 and charges. This article must therefore be hereby marked advertisement in accordance Jak3 associate with membrane-proximal regions of IL-2R␤ and with 18 U.S.C. Section 1734 solely to indicate this fact. IL-2R␥, respectively, and undergo catalytic activation following 1 This work was supported by operating grants from the Natural Sciences and Engi- ␤ ␥ neering Research Council of Canada and Cancer Research and Education Nova Sco- ligand-induced heterodimerization of IL-2R and IL-2R chains tia. H.Z. was the recipient of a fellowship from the Canadian Institutes for Health (21, 22). Jak1 and Jak3 activation leads to the phosphorylation of Research and the Nova Scotia Health Research Foundation. D.M.C. was the recipient at least three tyrosine residues (Y338,Y392, and Y510) on IL-2R of a postgraduate scholarship from Natural Sciences and Engineering Research Coun- cil of Canada. J.J.B. was supported by a Cancer Research and Education Trainee chains (23). Primed by these phosphorylation events, the IL-2R Award with funding from the Faculty of Medicine, Dalhousie University. C.Z. was complex generates two major proliferative signals. One of these supported by a fellowship from the China Scholarship Council. proliferative signals is mediated by the adaptor protein Shc (23, 2 Address correspondence and reprint requests to Dr. David W. Hoskin, Department 338 of Microbiology and Immunology, Dalhousie University Halifax, Nova Scotia, Can- 24), which binds to phosphorylated Y , undergoes tyrosine phos- ada B3H 1X5. E-mail address: [email protected] phorylation, and activates p42/p44-MAPK (also known as ERK) Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 933 and PI3K signaling pathways. The Grb2/Sos complex is recruited thine (DMPX), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), Rp-cAMPS, to Shc, and Sos activates the ERK pathway that up-regulates genes forskolin, and 8-bromo-cAMP (8-Br-cAMP) were purchased from such as c-fos and c-jun (25, 26). The PI3K signaling pathway, Sigma-Aldrich. which includes the serine/threonine kinase Akt (27), is activated Cell culture through recruitment of the adaptor protein GAB2 (28, 29). The second proliferative signal transduced by the IL-2R complex in- The IL-2-dependent CTLL-2 T cell line was obtained from the American Type Culture Collection (Manassas, VA). CTLL-2 cells were cultured in volves the transcription factor STAT5 (30, 31), which is recruited RPMI 1640 medium supplemented with 10% heat-inactivated FCS, 2 mM 510 to phosphorylated Y Shc (23), becomes tyrosine phosphory- L-glutamine, 100 U/ml penicillin, 100 ␮g/ml streptomycin (hereafter called lated, homo- and/or heterodimerizes with other STAT molecules, complete RPMI 1640 medium), and 20 U/ml IL-2 (R&D Systems, Min- and then directly translocates to the nucleus, where the complex neapolis, MN) in 250-ml culture flasks maintained at 37°C in a humidified 5% CO incubator. Spleen T cells were obtained from spleens of mice binds regulatory elements that control gene expression (32). The 2 sacrificed by cervical dislocation. Spleens were excised using aseptic tech- STAT5 family consists of highly homologous STAT5a and nique, and spleen cell suspensions were prepared in cold PBS (pH 7.4). STAT5b proteins that are coded for by two different STAT5 genes Following erythrocyte removal by osmotic shock, lymphocytes were (33). STAT5 plays a critical role in IL-2-driven T cell responses washed, resuspended in complete RPMI 1640 medium, and passaged because T lymphocytes from mutant mice with targeted deletions through a nylon wool column (Cellular Products, Buffalo, NY) to enrich for T lymphocytes. T cells were placed in wells of a 24-well flat-bottom tissue of STAT5a and/or STAT5b exhibit impaired proliferative re- culture plate (8 ϫ 106 cells/well) and induced to up-regulate IL-2R by sponses to IL-2 (34, 35).
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