cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Abstract

T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation.

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

“…In addition to these, the A2AR also has the capacity to couple to the Golf that has expression limited to the brain, while the A2BR [52] and the A3R can also bind to the Gq/11 proteins that promote phospholipase C (PLC) dependent intracellular Ca 2+ signaling [40,53,54]. Stimulation of adenylate cyclase (AC) by Gαs proteins induced by stimulation of A2AR/A2BR in T cells results in the localized accumulation of cyclic AMP (cAMP) in microdomains that occur at the immunological synapse (IS) (reviewed in [55]). cAMP can bind to the regulatory domains on type 1 Protein Kinase A (PKA) targeted to lipid rafts in the IS by Ezrin, an A-kinase binding protein (AKAP) [55].…”

“…Stimulation of adenylate cyclase (AC) by Gαs proteins induced by stimulation of A2AR/A2BR in T cells results in the localized accumulation of cyclic AMP (cAMP) in microdomains that occur at the immunological synapse (IS) (reviewed in [55]). cAMP can bind to the regulatory domains on type 1 Protein Kinase A (PKA) targeted to lipid rafts in the IS by Ezrin, an A-kinase binding protein (AKAP) [55]. This results in the phosphorylation of Src kinase, a negative regulator of Lck kinase, a key mediator of T-cell receptor (TCR) signaling activity (reviewed in [56]) [57][58][59].…”

Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity

“…Indeed, deletion and/or inhibition of components of the cAMP-PKA pathway modulate levels of other proteins that play a role in this pathway (Dupré et al, 2009;Erdogan and Houslay, 1997;Krumins and Gilman, 2006). In particular, we found that Coro1a À/À T cells expressed reduced amounts of the cAMP degrading enzyme PDE4, a central regulator of cAMP in T cells (Arumugham and Baldari, 2017). Furthermore, a PDE4 inhibitor, rolipram, phenocopied the coronin 1 depletion in an allograft rejection model.…”

Compartmentalized Cyclic AMP Production by the Bordetella pertussis and Bacillus anthracis Adenylate Cyclase Toxins Differentially Affects the Immune Synapse in T Lymphocytes

“…High concentrations of cyclic AMP (cAMP) are known to suppress the activation and function of immune cells ( 1 ). Several bacterial pathogens exploit this property to evade the immune response by producing cAMP-elevating toxins, as exemplified by the ADP-ribosylating toxins of Vibrio cholerae or Bordetella pertussis (PT), which promote the accumulation of cAMP by activating cellular Gs proteins or inactivating cellular Gi proteins, respectively ( 2 , 3 ), or the adenylate cyclase (AC) toxins produced by Bordetella pertussis (CyaA), Bacillus anthracis [edema toxin (ET)], or Pseudomonas aeruginosa (ExoY), which directly catalyze cAMP production in infected cells ( 4 – 6 ).…”