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The Molecular Mechanisms of cyclic AMP in regulation of immunity and tolerance

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Among miscellaneous functions, intracellular cyclic adenosine monophosphate (cAMP) is known to be a second messenger with potent immunomodulatory properties. While on the one side, cAMP is known to positively affect gene expression in T cells by the transcription factors cAMP responsive element binding (CREB) ...

Among miscellaneous functions, intracellular cyclic adenosine monophosphate (cAMP) is known to be a second messenger with potent immunomodulatory properties. While on the one side, cAMP is known to positively affect gene expression in T cells by the transcription factors cAMP responsive element binding (CREB) and cAMP responsive element modulator (CREM), this second messenger crucially contributes to suppression of inflammation and with that to the maintenance of peripheral tolerance. There is an emerging consensus that elevated levels of intracellular cAMP in thymus-derived regulatory T cells (tTregs) play a crucial role in tTreg cell-mediated suppression. Importantly, these high levels of intracellular cAMP, reaching nearly 100 fold higher concentrations in tTreg cells compared to conventional CD4+ T cells (Tcons), are caused by direct binding of Foxp3 to the phosphodiesterase 3b (Pde3b) gene. Moreover, Foxp3-mediated downregulation of miR-142-3p, which silences adenylyl cyclase (ADCY9) mRNA, leads to a further increase of intracellular cAMP levels in tTreg cells. Upon cell-to-cell contact between activated tTregs and Tcons elevated levels of cAMP in tTregs are transferred to Tcons via cell contact-dependent gap junction intercellular communications (GJIC). Importantly, this mechanism is not restricted exclusively on Tcons but various immune cell types may interact via GJIC with tTregs. GJIC is enabled by different connexins (Cx) among these Cx43 that forms Cx43/ZO-1/Ezrin/Protein kinase A (PKA) supramolecular complexes where ezrin targeted PKA controls its opening and closing by phosphorylation of Cx43. Alternatively, peripheral Tregs (pTregs) or Tcons can also contain elevated levels of intracellular cAMP after receptor-mediated stimulation by various agonists such as prostaglandin E2 (PGE2), histamine, serotonine, or agonists of adrenergic stimulation recognizing CD39/CD73 receptors. Depending on the spatiotemporal concentration, cAMP can either lead to activating or suppressing signals. Thus, cAMP-dependent signaling can trigger multifaceted molecular mechanisms acting in Tcons directly as well as indirectly. For instance, inducible cAMP early repressor (ICER) is a potent transcriptional inhibitor which can suppress the nuclear factor of activated T cell (NFAT)-mediated synthesis of IL-2 in activated Tcons. In addition to such suppressive effects mediated via ICER, cAMP can modulate the levels of surface-expressed cytotoxic T lymphocyte antigen-4 (CTLA-4) and its cognate B7 ligands on Tcons and/or antigen presenting cells (APCs), thus enabling a fine-tuning of its activities.

Hence, this Research Topic will give a comprehensive overview of recent research on the influence of cAMP-mediated mechanisms concerning the regulation/modulation especially of the CD4+ T cell family.


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