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 a re currently explained by direct intracellular lymphotoxicity of Ado m etabolites. In support of the alternative, ''signaling'' mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell rec eptor (TCR)triggered effector functions of T Lymphocytes including the TCR-triggered Fast mRNA up-regulation in cytotoxic T lymphocytes. Str ong evidence against the intracellular lymphotoxicity of Ado (and in s upport of the signaling model) is provided by abrogation of TCR-trigge red growth inhibition in Ado exposed T cells. The brief exposure to Ad o was sufficient to observe inhibition of TCR-triggered effector funct ions. The ''memory'' of T cells to exposure to extAdo is best explaine d by sustained increases in cAMP. Selective agonist (CGS21680) and ant agonist (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 an d TCR in both directions support the possible role of A(2A) receptors in mechanisms of extAdo-mediated immunosuppression in vivo under adeno sine deaminase deficiency and hypoxic conditions in, e.g., solid tumor s.