Regulatory T-Cell-Mediated Suppression of Conventional T-Cells and Dendritic Cells by Different cAMP Intracellular Pathways

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.

Propentofylline, phosphodiesterase and adenosine reuptake inhibitor modulates lymphocyte subsets and lymphocyte activity after in-vivo administration in non-immunized and SRBC-immunized mice

“…Tregs exert the suppressive action on effector T cells directly or through dendritic cells. Activated Tregs accumulate cAMP that may be transferred from Tregs to target cells through gap junctions . In‐vitro and in‐vivo studies published by Bopp et al .…”

“…Activated Tregs accumulate cAMP that may be transferred from Tregs to target cells through gap junctions. [30,31] In-vitro and in-vivo studies published by Bopp et al [24] showed that Tregs combined with rolipram synergistically enhanced cAMP accumulation in Th2 cells, decreased IL-4 production by these cells and reduced inflammation and airway hyperresponsiveness in mice with experimentally induced asthma. In our study, propentofylline-induced reduction in IL-5 secretion might have resulted from intensification of the inhibitory effect of Tregs on Th2 lymphocytes.…”

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

“…We will also discuss the changes that have been brought into our thinking by studies on cAMP compartmentalization and a possible new role of cAMP microdomains in naive T cell activation. For a discussion of the role of cAMP in T reg -mediated peripheral tolerance, the reader is referred to recent reviews by Rueda et al [10] and Klein and Bopp [11].…”

Regulatory T cell subsets in peripheral blood of HIV-infected patients with discordant response to antiretroviral therapy

“…Необходимо отметить, что Treg проявляют супрессивную активность не только в отношении CD4 + Т-клеток, но в том числе и среди CD8 + Тлимфоцитов и клеток врожденного иммунитета [23,28]. Важным является то, что размер популяций названных выше клеток значительно превосходит численность самих регуляторных Т-лимфоцитов.…”