cAMP and AKAPs
The common and versatile second messenger cyclic adenosine monophosphate (cAMP) is derived from adenosine triphosphate (ATP) and controls numerous cellular processes. Cyclic AMP has been implicated in signalling downstream of a large number of hormones, neurotransmitters, prostaglandins and chemokines and is known to be a potent inhibitor of T cell proliferation and cytokine production. Although the biological effects of cAMP are mainly mediated by the activation of cAMP-dependent protein kinase A (PKA), cAMP is also involved in the activation of cAMP-gated ion channels (CNGs) and cAMP-regulated guanine exchange factors (EPACs).
A-kinase anchoring proteins (AKAPs) are scaffolding proteins that both facilitate and localise signalling within the cell by assembling the signalling elements in close proximity to each other. It is estimated that there are more than 75 AKAP proteins, 50 of which have thus far been characterised. Although multiple receptors and targets use cAMP as a second messenger, signalling specificity is obtained due to targeting of PKA to sub-cellular compartments through interaction with AKAPs.
Intracellular signalling is characterised by spatial and temporal integration of multiple signalling cascades into signalling networks. The fine-tuning of a functional response to an external stimulus requires mechanisms of sub-cellular compartmentalization of the signalling events, mechanisms of activation and signal generation and eventually, signal termination. The sub-cellular compartmentalization of signalling events depends on anchoring and scaffolding molecules that serve to organize the signalling molecules into signal complexes in order to facilitate protein-protein interactions that efficiently and discretely transduce the signal. Consequently, intracellular signalling events are characterized by dynamic signalling profiles that involve highly organized protein complexes that interact and transmit post-translational modifications in order to convey a signal precisely and thereby generate a distinct cellular response.
Modulation of proximal TCR signalling by cAMP and PKA. Generation of local pools of cAMP is able to attenuate proximal TCR signalling by activating a cAMP-PKA-Csk inhibitory pathway. Ezrin acts as an AKAP and targets PKA type I to lipid rafts where it can phosphorylate and activate Csk. Thus, increased cAMP levels lead to activation of PKA, phosphorylation and activation of Csk and inhibition of Src family protein tyrosine kinases Lck. Figure: BiO/ UiO.
Regulatory T cells
Human regulatory T cells (Tregs) comprise 5-10% of the peripheral CD4+ T cell pool and are recognised by constitutive expression of CD25 (IL-2Rα) and the transcription factor FOXP3. Tregs are functionally characterised by their ability to suppress effector T cells and they play an essential role in maintaining peripheral immunological tolerance.
Natural vs adaptive Tregs
Naturally occurring Tregs are derived from the thymus and suppress effector T cells in a cell-cell contact-dependent manner, where as adaptive or peripherally induced Tregs (iTregs) originate from naïve T cells or effector T cells that undergo a phenotypic switch during T cell activation and differentiation. iTregs acquire immunosuppressive properties at the site of antigen exposure, suppressing effector cells by both cell-cell contact-dependent mechanisms and by cytokines. iTregs are short-lived and are considered to represent an important mechanism that turns off the immune response after an acute infection in addition to limit the immune reactivity during chronic immune responses to prevent immune-related tissue destruction (see figure above). However, in cancer the induction of iTregs that inhibit anti-tumor immunity is a dysfunctional response. Naturally occurring Tregs, on the other hand, represent a stable T cell phenotype and are considered to be a pivotal mechanism for maintaining peripheral immune self-tolerance.
Tregs also contribute to and are involved in various immune-related diseases, including cancer and chronic infectious diseases. In cancer, Tregs are important contributors to the immunosuppressive microenvironment that surrounds most solid malignant tumors, thereby inhibiting anti-tumour immune activity and preventing an efficient anti-tumour immune response. Thus, Tregs represent an attractive target for immune therapy.