Abstract
Regulatory T-cells (Tregs) mediate their suppressive action by acting directly on conventional T-cells (Tcons) or dendritic cells (DCs). One mechanism of Treg suppression is the increase of cyclic adenosine 3′,5′-monophosphate (cAMP) levels in target cells. Tregs utilize cAMP to control Tcon responses, such as proliferation and cytokine production. Tregs also exert their suppression on DCs, diminishing DC immunogenicity by downmodulating the expression of costimulatory molecules and actin polymerization at the immunological synapse. The Treg-mediated usage of cAMP occurs through two major mechanisms. The first involves the Treg-mediated influx of cAMP in target cells through gap junctions. The second is the conversion of adenosine triphosphate into adenosine by the ectonucleases CD39 and CD73 present on the surface of Tregs. Adenosine then binds to receptors on the surface of target cells, leading to increased intracellular cAMP levels in these targets. Downstream, cAMP can activate the canonical protein kinase A (PKA) pathway and the exchange protein activated by cyclic AMP (EPAC) non-canonical pathway. In this review, we discuss the most recent findings related to cAMP activation of PKA and EPAC, which are implicated in Treg homeostasis as well as the functional alterations induced by cAMP in cellular targets of Treg suppression.
Highlights
Regulatory T-cells (Tregs), first described by Sakaguchi et al in 1995 [1], are essential to maintain immune homeostasis and protection against autoimmunity
It is accepted that the cAMP-dependent intracellular signaling induced by Tregs in target cells is much more complex than initially assumed, and the classic protein kinase A (PKA) pathway is only part of the story
Both human and murine Tregs mediate suppression indistinctly by cAMP influx and/or the CD39/adenosine pathway, the downstream pathways differ in Tcons and dendritic cells (DCs)
Summary
Regulatory T-cells (Tregs), first described by Sakaguchi et al in 1995 [1], are essential to maintain immune homeostasis and protection against autoimmunity. The differential expression and activation of ACs and PDEs in Tregs and Tcons explain the high level of intracellular cAMP in murine and human Tregs compared to Tcons [8, 18, 19]. An isoform of PDE (PDE3b) is one of the most FOXP3-repressed genes in murine Treg [21], resulting in low cAMP degradation and subsequent elevation of cAMP levels in Tregs (Figure 1A). The binding of adenosine to its G protein-coupled receptors (GPCRs) on target cells leads to the stimulatory G protein alpha subunit (Gsα) directly activating ACs and generating cAMP [31,32,33]. The A2A receptor is expressed by resting and activated Tregs [30] and treatment for Tregs by adenosine analogs increased their cAMP levels [46] (Figure 1A). The fact that Tregs produce and respond to adenosine suggests that adenosine might act as an autocrine factor to optimize Treg anti-inflammatory function, as proposed by Ernst et al [48]
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