Activation-induced cell death (AICD) is initiated by T-cell receptor (TCR) restimulation of already activated and expanded peripheral T cells and is mediated through Fas/Fas ligand (FasL) interactions. Adenosine is a purine nucleoside signaling molecule, and its immunomodulatory effects are mediated by 4 G-protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In this study, we investigated the role of A(2A) receptors in regulating CD4(+) T lymphocyte AICD. Our results showed that the selective A(2A) receptor agonist CGS21680 (EC(50)=15.2-32.6 nM) rescued mouse CD4(+) hybridomas and human Jurkat cells from AICD and that this effect was reversed by the selective A(2A) receptor antagonist ZM241385 (EC(50)=2.3 nM). CGS21680 decreased phosphatidylserine exposure on the membrane, as well as the cleavage of caspase-3, caspase-8 and poly(ADP-ribose) polymerase indicating that A(2A) receptor stimulation blocks the extrinsic apoptotic pathway. In addition, CGS21680 attenuated both Fas and FasL mRNA expression. This decrease in FasL expression was associated with decreased activation of the transcription factor systems NF-kappaB, NF-ATp, early growth response (Egr)-1, and Egr-3. The antiapoptotic effect of A(2A) receptor stimulation was mediated by protein kinase A. Together, these results demonstrate that A(2A) receptor activation suppresses the AICD of peripheral T cells.