Adenosine induced immunosuppression: The role of the adenosine receptor-adenylate cyclase interaction in the alteration of T-lymphocyte surface phenotype and immunoregulatory function

Abstract

Adenosine (1 μM at 37°C) rapidly modulates the expression of T-lymphocyte surface antigens (OKT4 and OKT8) and Fcγ receptors, and increases T-suppressor activity for pokeweed mitogen driven in vitro immunoglobulin synthesis. The adenosine induced increased OKT8 expression developed more slowly; increased Fcγ expression was maximal at 30 min after initiation of incubation with adenosine. Adenosine, 2-chloroadenosine and adenosine in the presence of nitrobenzylthioinosine (NBTI) induced the decrease in OKT4 expression. In contrast only adenosine induced the enhancement of OKT8 and Fcγ receptor expression. Neither 2-chloroadenosine, a poorly transported analog, nor adenosine in the presence of the adenosine transport inhibitor NBTI were capable of enhancing OKT8 or Fcγ receptor expression. Adenosine was shown to cause a rapid biphasic increase cAMP, while 2-chloroadenosine and adenosine with NBTI induces a prolonged elevation to cAMP. Similarly isoproteranol which induces a sustained elevation in cAMP suppressed the adenosine induced increases in OKT8 and Fcγ receptor expression. Incubation of T-helper/inducer lymphocytes with 1 μM adenosine for 30 min at 37°C caused the loss of T-helper function; this loss of T-helper activity has previously been shown to result from the activation of T-suppressor cells. The loss of T-helper function was blocked by the simultaneous addition of (1) isobutylmethylxanthine, an R site adenosine receptor antagonist, or (2) NBTI, an adenosine transport inhibitor. Moreover, 2-chloroadenosine could not induce loss of T-helper function. These data indicate that the loss of OKT4 expression induced by adenosine is caused by the rapid rise in cAMP due to adenosine interaction with Ra stimulatory adenosine receptors. Exogenous cAMP was found to cause a maximal loss in OKT4 expression at 10 −12 M. In contrast adenosine enhanced expression of OKT8 and Fcγ receptors was inhibited by persistent cAMP elevation and required entry to adenosine into the cell as well as a decline in cAMP. The development of immunosuppressive activity was shown to require both stimulation of the Ra site, as well as entry of adenosine into the cell.