Editorial: The Molecular Mechanisms of Cyclic AMP in Regulation of Immunity and Tolerance

The inhibitory effects of the second messenger cyclic adenosine monophosphate (cAMP) on T-cell proliferation and effector functions have been originally reported by Gary Kammer in 1988 (1). At that time, little had been known about the mechanisms by which the inhibitory effects occur. The situation changed upon the discovery of the hallmark of cAMP responsive transcription—cAMP-responsive element binding (CREB) protein by Jim Hoeffler in Joel Habener's lab at Massachusetts General Hospital (Boston, MA, USA) (2). However, it was still unclear how stimulation of the cAMP-dependent signaling pathway could exert an inhibitory effect on T-cell proliferation and effector functions. Soon after joining Joel Habener's lab, I started to collaborate with Anna-Lena Spetz in Jack Strominger's lab at the Dana-Farber Cancer Institute (Boston, MA, USA). Anna-Lena provided human thymus glands obtained from children undergoing corrective heart surgery and fractionated them over discontinuous Percoll gradients in order to separate medullary from cortical thymocytes. Our analyses confirmed that cAMP-dependent signaling is likely to play an important role during intrathymic T cell development since unexpectedly high intracellular levels of cAMP were formed in more mature medullary thymocytes in the presence of forskolin or prostaglandin E2. This ability to generate cAMP correlated with the expression of the potent transcriptional repressor ICER (inducible cAMP early repressor) and was retained by the majority of mature peripheral blood T lymphocytes (3). Induction of ICER was claimed to be exclusive to hypothalamic–pituitary–gonadal axis by Paolo Sassone-Corsi (4); however, our discovery of robust ICER expression in the human immune system came as a surprise (3). At the same time, Jeff Leiden demonstrated that thymocytes transgenic for a dominant negative isoform of CREB (DN CREB) were unable to phosphorylate the critical Ser at position 119 displayed after T cell activation. This functional defect resulted in a profound prolifera-tive consequence characterized by markedly decreased interleukin-2 (IL-2) production (5). Clearly, a single point mutation of the critical Ser 119 disabled activation domain in DN CREB acted to a similar extent as ICER, which lacks this activation domain entirely, and thus served as dominant negative repressor of IL-2 expression [note added in proof (3)]. Soon afterward, Ron Schwartz at the National Institutes of Health (Bethesda, MD, USA) redefined T cell anergy as failure to produce IL-2 via CREB/CREM-mediated transcriptional attenuation (6). Since ICER represents the only cAMP responsive subfamily of four isoforms (4), we concluded that at least part of inhibitory effects of cAMP on …