Cyclic-AMP in T cell mitogenesis: Inhibition of high-affinity interleukin-2 receptors

Diane Sue Krause, University of Pennsylvania


In vivo, lymphocytes are activated by antigen, and maintained in an active state by lymphokines. Little is known of the mechanism by which T cells are inactivated. The purpose of this study was to elucidate how elevated intracellular cAMP inhibits the activation of T lymphocytes. Because the whole-cell potassium conductance increases when a T cell is activated, and agents that block the potassium channel inhibit T cell proliferation, I tested the hypothesis that elevated (cAMP) $\sb{\rm i}$ inhibits T cell activation by modulating this potassium conductance. I showed that elevated (cAMP) $\sb{\rm i}$ did not affect the voltage-dependent K$\sp+$ conductance of quiescent T cells, indicating that inhibition of T cell activation by cAMP is not mediated by a change channel conductance. However, forskolin, a direct activator of adenylate cyclase, did directly inhibit the K$\sp+$ conductance. Using cells stimulated in serum-free medium with anti-CD3 antibody and IL2, I showed that elevated (cAMP) $\sb{\rm i}$ (mimicked by CPT-cAMP or induced by the physiological agonist PGE$\sb2$) directly inhibited mitogen-induced $\sp3$H-thymidine incorporation by peripheral blood mononuclear cells (PBMC), purified T cells, and isolated CD4$\sp+$ and CD8$\sp+$ T cell subpopulations. One mechanism responsible for this inhibition was decreased IL2 receptor expression as demonstrated by the inhibited (1) expression of both high and low affinity IL2 receptors; (2) plasma membrane expression of both p55 and p75 subunits of the IL2 receptor; and (3) expression of p55 mRNA, but not p75 mRNA. The decrease in p55 mRNA was not due to enhanced mRNA metabolism. I conclude that elevated (cAMP) $\sb{\rm i}$, acting directly within T cells, inhibits mitogenesis by decreasing IL2 receptor expression. I discuss the possible physiological relevance for the multiple stages of T cell activation that are sensitive to elevated (cAMP) $\sb{\rm i}$.

Subject Area

Molecular biology|Biology

Recommended Citation

Krause, Diane Sue, "Cyclic-AMP in T cell mitogenesis: Inhibition of high-affinity interleukin-2 receptors" (1990). Dissertations available from ProQuest. AAI9112590.