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A2B Adenosine Receptors and T Cell Activation 493 Journal of Cell Science 112, 491-502 (1999) 491 Printed in Great Britain © The Company of Biologists Limited 1999 JCS0069 Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation Maribel Mirabet1, Carolina Herrera1, Oscar J. Cordero2, Josefa Mallol1, Carmen Lluis1 and Rafael Franco1,* 1Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Barcelona, Barcelona, Catalonia, Spain 2Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Santiago de Compostela, Spain *Author for correspondence (e-mail: [email protected]; homepage: www.bq.ub.es/recep/franco.html) Accepted 9 December 1998; published on WWW 25 January 1999 SUMMARY Extracellular adenosine has a key role in the development A2BRs but not of A2A receptors in these human cells. The and function of the cells of the immune system. Many of percentage of A2BR-expressing cells was similar in the the adenosine actions seem to be mediated by specific CD4+ or CD8+ T cell subpopulations. Interestingly surface receptors positively coupled to adenylate cyclase: activation signals delivered by either phytohemagglutinin A2A and A2B. Despite the fact that A2A receptors (A2ARs) or anti-T cell receptor/CD3 complex antibodies led to a can be easily studied due to the availability of the specific significant increase in both the percentage of cells agonist CGS21680, a pharmacological and physiological expressing the receptor and the intensity of the labeling. characterization of adenosine A2B receptors (A2BRs) in These receptors are functional since interleukin-2 lymphocytes has not been possible due to the lack of production in these cells is reduced by NECA but not by R- suitable reagents. Here we report the generation and PIA or CGS21680. These results show that A2BR characterization of a polyclonal antipeptide antibody expression is regulated in T cell activation and suggest that raised against the third extracellular loop of the A2BR the role of adenosine in lymphocyte deactivation is human clone which is useful for immunocytochemical mediated by A2BRs. + studies. This antibody has permitted the detection of A2BR cells in lymphocyte samples isolated from human peripheral blood. The pharmacology of cAMP-producing Key words: Adenosine receptor, T cell activation, Antipeptide compounds is consistent with the presence of functional antibody INTRODUCTION 1992; Linden et al., 1993; Salvatore et al., 1993; Tucker and Linden, 1993). All these P1 purinoceptors belong to the Adenosine, acting outside the cell, exerts potent actions on a superfamily of G protein-coupled receptors having seven wide variety of physiological systems, including the nervous, transmembrane domains. cardiovascular, gastrointestinal, urogenital, respiratory, and The relevance of adenosine for the development and lymphatic systems. Many of these actions are mediated via function of the immune system is deduced from the severe specific receptors named P1 purinoceptors (Daly et al., 1983). combined immunodeficiency syndrome (SCID) associated From studies on the variation of adenylate cyclase activity with the congenital defect of adenosine deaminase, the produced by adenosine analogues, and on the rank order of enzyme which degrades the nucleoside. In adenosine potency of agonists, P1 purinoceptors were subdivided into deaminase-deficient children, elevated levels of adenosine two classes: A1, which mediate decreases in cAMP levels, (and 2′-deoxyadenosine) are found in body fluids. Several and A2, which mediate increases in cAMP levels (Van mechanisms whereby adenosine deaminase deficiency may Calcker et al., 1979; Londos et al., 1980). The affect the development and function of lymphoid cells have pharmacological characterization of the A2 subtype in been suggested but none can satisfactorily explain all the different tissues led to the finding of two different populations relationships found in SCID. Most of the proposed which were named A2A and A2B, and had very different mechanisms (see Hershfield and Mitchell, 1989, for review) affinities for the agonist CGS21680. It is now becoming clear have rested upon the assumption that accumulation of the two that the subtypes of adenosine receptors can be linked to a physiological substrates of adenosine deaminase, adenosine variety of signal transduction systems apart from adenylate and 2′-deoxyadenosine, are toxic for lymphocytes (Franco et cyclase (Stiles, 1992; Linden, 1994; Schubert et al., 1994; al., 1998, and references therein). There is recent data Fredholm, 1995). These receptor subtypes (A1, A2A and A2B) suggesting that signaling through purinergic receptors in as well as another member of the family, which was lymphocyte and lymphocyte precursors may contribute to the discovered more recently (A3), have been cloned (Zhou et al., pathogenesis of adenosine deaminase-related SCID (Apasov 492 M. Mirabet and others et al., 1997; Resta and Thompson, 1997). On the other hand, Cells and culture conditions adenosine receptors seem to be involved in the regulation by Chinese hamster ovary (CHO) cells transfected with cDNA coding for adenosine of T-cell receptor-triggered activation-related the human A2B adenosine receptor (Pierce et al., 1992) were kindly events, such as antibody production, cell proliferation, IL-2 provided by Dr Peter R. Schofield from the Garvan Institute of production, upregulation of IL-2 receptor α-chain (CD25) Medical Research at St Vincent’s Hospital in Sidney, Australia. and lymphocyte-mediated cytolysis (Wolberg et al., 1975; Chinese hamster ovary (CHO) cells transfected with a cDNA coding Dos Reis et al., 1986; Antonysamy et al., 1995; Huang et al., for a recombinant protein composed of the human A2A adenosine 1997). Adenosine receptors regulating these different aspects receptor containing the M2 flag in its C-terminal end (Rivkees et al., 1995) were kindly provided by Dr Scott A. Rivkees from Yale of lymphoid function are those leading to increases in cAMP University, New Haven, CT, USA. Transfected CHO cells were grown levels, i.e. A2AR and/or A2BR (Dos Reis et al., 1986). In fact, in Dulbecco’s modified Eagle’s medium/Hams F12 nutrient mixture adenosine and 2-chloroadenosine lead to increases in human (1:1) containing 10% (v:v) fetal calf serum, 2 mM L-glutamine, lymphocyte cAMP levels (Marone et al., 1978; Dinjens et al., antibiotics (100 i.u./ml penicillin, 100 µg/ml streptomycin and 0.25 1986). Recently, Huang et al. (1997) have shown that A2ARs µg/ml fungizone and 1.6 mg/ml of the neomycin analog G-418), at are involved in adenosine-mediated inhibition of murine T- 37°C in an humid atmosphere of 5% CO2. Wild-type CHO cells were cell activation and expansion. In these events the role of cultured in the same conditions described for transfected cells but in A2BRs has not been established due to the lack of suitable the absence of G-418. Jurkat cells were maintained in RPMI 1640 tools for their study. In this paper we describe the generation medium supplemented with 10% (v:v) fetal bovine serum, 2 mM L- and characterization of two polyclonal antipeptide antibodies glutamine and antibiotics at 37°C under a 5% CO2 atmosphere. HEP- G2 cells were cultured in DMEM supplemented with 4.5 g/l glucose raised against different regions of the A2BR human clone. and 10% fetal serum. All the culture reagents were from Gibco (Grand One of these antibodies has proven to be inestimable for the Island, NY, USA). identification of A2BR-expressing human blood lymphocytes. Peripheral blood mononuclear cells (PBMC) from healthy donors Further analysis of these cells have shown that the expression were isolated from buffy coats (kindly provided by Dr Hernández of A2BR is regulated in T cell activation events thus indicating from the Banco de Sangre of the Hospital General Vall d’Hebrón de that A2BRs are involved in the regulation by adenosine of Barcelona) using the Ficoll gradient method described by Boyum signaling processes occurring in human lymphocytes. (1968). Further purification of lymphocytes (PBL) from PBMC was Furthermore, upregulated A2BRs are functional and elicit performed by depletion of contaminating cells by adherence to plastic significant reductions in interleukin-2 production. These plates. An homogeneous population corresponding to total results are similar to those found in murine macrophages in lymphocytes was observed according to forward and side light scatter γ parameters by flow cytometry analysis with less than 7% of which A2BRs are upregulated in response to interferon- . As contaminating monocytes. PBMC or PBL were split at 106 cells/ml we described here for T lymphocytes, adenosine, acting and cultured in the same conditions as described above for Jurkat through A2BRs, contributes to the deactivation of cells. In vitro activation of cells was carried out with 1 µg/ml macrophages since it reduces the upregulation of MHC phytohemagglutinin (PHA; Difco Laboratories, Detroit, MI, USA) or class II molecules, the activity of nitric oxid synthase or was conducted in well plates coated with OKT3 antibody. For OKT3 the production of pro-inflammatory cytokines (Xaus et al., antibody immobilization, 300 µl of 10 mM PBS, pH 7.4, containing 1999). 2.5 µg/ml purified OKT3 antibody were placed for 3 hours at 37°C in a 24-well flat bottom plate. After 2 washes with 2 ml of cold PBS, cells were added to wells at a density of 106 cells/ml to begin the MATERIALS AND METHODS activation experiments. Anti-A2B adenosine receptor antibody generation and Materials purification
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