Memory of extracellular adenosine A(2A) purinergic receptor-mediated signaling in murine T cells

Accumulation of extracellular and intracellular adenosine (Ado) under hypoxic conditions or in the absence of adenosine deaminase results in lymphocyte depletion and in severe combined immunodeficiency, which are currently explained by direct intracellular lymphotoxicity of Ado metabolites. In support of the alternative, ''signaling'' mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell receptor (TCR)triggered effector functions of T Lymphocytes including the TCR-triggered Fast mRNA up-regulation in cytotoxic T lymphocytes. Strong evidence against the intracellular lymphotoxicity of Ado (and in support of the signaling model) is provided by abrogation of TCR-triggered growth inhibition in Ado exposed T cells. The brief exposure to Ado was sufficient to observe inhibition of TCR-triggered effector functions. The ''memory'' of T cells to exposure to extAdo is best explained by sustained increases in cAMP. Selective agonist (CGS21680) and antagonist (ZM241385) of A(2A) adenosine receptor were used in functional assays and cDNA probes for different sybtypes of adenosine receptors were used in Northern blot studies. A(2A) receptors are identified as the predominantly expressed subtype of G(s)-coupled Ado receptors in T cells, The demonstration of cross-talk between the A(2A) receptors and TCR in both directions support the possible role of A(2A) receptors in mechanisms of extAdo-mediated immunosuppression in vivo under adenosine deaminase deficiency and hypoxic conditions in, e.g., solid tumors.