Studies of expression and possible functional role of purinergic receptorsin cell-mediated immunity: Experimental approaches, controls, and caveats

The expression of purinergic receptors for the physiologically abundant mol ecules of extracellular ATP (eATP) and e adenosine (Ado) in lymphoid cells of T-cell lineage has been demonstrated convincingly in short-term biochemi cal and pharmacologic assays. T-cell differentiation-related expression of P2X(7) receptors for ATP was demonstrated in murine T-cells, whereas A(2A) adenosine receptors were shown to be responsible for observed increases in cAMP during incubation of T-cells with adenosine. The possibility of a feed -back regulation mechanism of T-cell functions with eATP is suggested by pa tterns of expression of purinergic receptors, which may follow the immediat e early response genes. The functioning of adenosine receptors was suggeste d to be involved in the pathogenesis of human disease, adenosine deaminase severe combined immunodeficiency. Extracellular ATP and adenosine affect T- cell differentiation and effector functions in vitro; however, convincing e vidence of purinergic modulation of immune response in vivo or in long-term immunoassays in vitro is still lacking. An explanation of the effects of e ATP and eAdo on T-lymphocytes' differentiation and effector functions must include considerations of (1) possible intracellular effects of ATP, adenos ine, and/or their metabolites; 2) the effects of eAdo- and eATP-triggered t ransmembrane signaling through P1 and P2 classes of purinergic receptors, r espectively; and (3) the reversible phosphorylation of extracellular domain s of functionally important cell surface proteins by ATP. The use of existi ng agonists and antagonists of purinergic receptors and of ATP and of adeno sine-hydrolyzing enzymes has some limited mechanistic implications, but it may lead to artifacts due to uncertainties between extracellular and intrac ellular effects of these reagents and the possible presence of contaminants in commercial preparations of enzymes. Drug Dev. Res. 45:229-244, 1998. Pu blished 1998 Wiley-Liss, Inc.dagger