ROLE OF A2A EXTRACELLULAR ADENOSINE RECEPTOR-MEDIATED SIGNALING IN ADENOSINE-MEDIATED INHIBITION OF T-CELL ACTIVATION AND EXPANSION

Accumulation of adenosine and of deoxyadenosine in the absence of aden osine deaminase activity (ADA) activity results in lymphocyte depletio n and in severe combined immunodeficiency (ADA SCID), which is current ly explained by direct cell death-causing effects of intracellular pro ducts of adenosine metabolism, We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansio n by extracellular adenosine mediated signaling through purinergic rec eptors, The strong inhibition of the T-cell receptor (TCR)-triggered p roliferation and of upregulation of interleukin-2 receptor alpha chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extra cellular adenosine (Ado) are likely to be mediated by A2a receptor-med iated signaling rather than by intracellular toxicity of adenosine cat abolites, because (1) poorly metabolized adenosine analogs cause the a ccumulation of cAMP and strong inhibition of TCR-triggered CD25 upregu lation; (2) the A2a, but not the A? or A3, receptors are the major exp ressed and functionally coupled adenosine receptors in mouse periphera l T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the s pecific 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 up regulation and splenocyte proliferation. These studies suggest the pos sible Pole of adenosine receptors in the regulation of lymphocyte expa nsion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target. (C) 1997 by T he American Society of Hematology.