Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion

Abstract

Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansion by extracellular adenosine-mediated signaling through purinergic receptors. The strong inhibition of the T-cell receptor (TCR)-triggered proliferation and of upregulation of interleukin-2 receptor α chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extracellular adenosine (Ado) are likely to be mediated by A2a receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites, because (1) poorly metabolized adenosine analogs cause the accumulation of cAMP and strong inhibition of TCR-triggered CD25 upregulation; (2) the A2a, but not the A1 or A3, receptors are the major expressed and functionally coupled adenosine receptors in mouse peripheral T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the specific agonist of A2a receptor, CGS21680, induces increases in [cAMP]i in lymphocytes, whereas the specific antagonist of A2a receptor, CSC, inhibits the effects of Ado and CGS21680; and (4) the increases in [cAMP]i mimic the adenosine-induced inhibition of TCR-triggered CD25 upregulation and splenocyte proliferation. These studies suggest the possible role of adenosine receptors in the regulation of lymphocyte expansion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target.

Adenosine A2Areceptor activation protects CD4+T lymphocytes against activation‐induced cell death

“…Extracellular adenosine exerts a variety of immunomodulatory effects, which are mediated by 4 G-protein-coupled receptor subtypes: A 1 , A 2A , A 2B , and A 3 (6 -11). Although resting mouse and human T lymphocytes express all four adenosine receptors, A 2A receptors (A 2A Rs) are the dominant adenosine receptors in governing lymphocyte responses (7,(12)(13)(14)(15)(16)(17)(18). A 2A R stimulation inhibits TCR-mediated proliferation, cytokine production, and up-regulation of positive costimulatory molecules (reviewed in ref.…”

Adenosine A2Areceptor activation and macrophage‐mediated experimental glomerulonephritis

“…[32][33][34][35]. Adenosine can inhibit proliferation, activation, and production of inflammatory cytokines in peripheral T cells, it also can enhance the production of anti-inflammatory cytokines (36,37).…”

Naturally occurring regulatory T cells: markers, mechanisms, and manipulation

“…The finding that nTregs express high levels of CD39 and CD73 (57,58), two ectonucleotidases involved in the generation of extracellular adenosine, has led to the assumption that Treg-released adenosine might play a role in the suppressive function of Tregs. Adenosine is known to exert immunosuppressive activity on T cells via ligation of adenosine receptors, including A 2A R (136), which leads to an increase in intracellular cAMP. Indeed, nTregs express constitutively high levels of A 2A R, and Teffs rapidly up-regulate A 2A R on activation.…”