The Journal of Immunology, 2005, 174: 1073-1080.
Copyright © 2005 by The American Association of Immunologists
A2A Adenosine Receptor Induction Inhibits IFN-
Production in Murine CD4+ T Cells1
Courtney M. Lappas2,*,
Jayson M. Rieger
and
Joel Linden
* Departments of Pharmacology and
Medicine, University of Virginia, Charlottesville, VA 22908; and
Adenosine Therapeutics, LLC, Charlottesville, VA 22911
Incubation of purified C57BL/6 murine CD4+ T lymphocytes with anti-CD3 mAb serves as a model of TCR-mediated activation and results in increased IFN-
production and cell surface expression of CD25 and CD69. We demonstrate here that signaling through the TCR causes a rapid (4-h) 5-fold increase in A2A adenosine receptor (AR) mRNA, which is correlated with a significant increase in the efficacy of A2AAR-mediated cAMP accumulation in these cells. A2AAR activation reduces TCR-mediated production of IFN- by 98% with a potency order of 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}cyclohexanecarboxylic acid methyl ester (ATL146e; EC50 = 0.19 ± 0.03 nM) > 4-{3-[6-amino-9-(5-cyclopropyl-carbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}piperidine-1-carboxylic acid methyl ester (ATL313; 0.43 ± 0.06 nM) > 5'-N-ethylcarboxamidoadenosine (3.5 ± 0.77 nM) > 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680 7.2 ± 1.4 nM) >> N6-cyclohexyladenosine (110 ± 33 nM) > 2-chloro-N6-(3-iodobenzyl)-5'-N-methylcarboxamide (390 ± 160 nM), similar to the potency order to compete for radioligand binding to the recombinant murine A2AAR but not the A3AR. The selective A2AAR antagonist, 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385), inhibits the effect of ATL146e with a pA2 of 0.34 nM and also inhibits the effects of N6-cyclohexyl-adenosine and 2-chloro-N6-(3-iodobenzyl)-5'-N-methylcarboxamide. In CD4+ T cells derived from A2AAR–/– and A2AAR+/– mice, the IFN- release response to ATL146e is reduced by 100 and 50%, respectively, indicative of a gene dose effect. The response of T cells to the phosphodiesterase inhibitor, 4-(3'-cyclopentyloxy-4'-methoxyphenyl)-2-pyrrolidone (rolipram), is not affected by A2AAR deletion. We conclude that the rapid induction of the A2AAR mRNA in T cells provides a mechanism for limiting T cell activation and secondary macrophage activation in inflamed tissues.
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