Cyclic adenosine monophosphate is a key component of regulatory T cell–mediated suppression

Abstract

Naturally occurring regulatory T cells (T reg cells) are a thymus-derived subset of T cells, which are crucial for the maintenance of peripheral tolerance by controlling potentially autoreactive T cells. However, the underlying molecular mechanisms of this strictly cell contact–dependent process are still elusive. Here we show that naturally occurring T reg cells harbor high levels of cyclic adenosine monophosphate (cAMP). This second messenger is known to be a potent inhibitor of proliferation and interleukin 2 synthesis in T cells. Upon coactivation with naturally occurring T reg cells the cAMP content of responder T cells is also strongly increased. Furthermore, we demonstrate that naturally occurring T reg cells and conventional T cells communicate via cell contact–dependent gap junction formation. The suppressive activity of naturally occurring T reg cells is abolished by a cAMP antagonist as well as by a gap junction inhibitor, which blocks the cell contact–dependent transfer of cAMP to responder T cells. Accordingly, our results suggest that cAMP is crucial for naturally occurring T reg cell–mediated suppression and traverses membranes via gap junctions. Hence, naturally occurring T reg cells unexpectedly may control the immune regulatory network by a well-known mechanism based on the intercellular transport of cAMP via gap junctions.

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

“…The transport of cAMP between Tregs and other T cells has been identified and confirmed in several studies. 12,34,35 Our study showed that low-dose CY changes the intracellular cAMP concentrations of immune cells, indicating that the cAMP signaling pathway is critical to Treg-mediated immune evasion and CY-induced Treg suppression. Furthermore, our data demonstrate that cAMPdependent signal transduction directly attenuates the production of IL-2 in CD4 1 Teff cells.…”

“…Many studies have demonstrated that cAMP is a potent inhibitor of IL-2 production and the subsequent proliferation of CD4 T cells. 12,33 This finding was later confirmed by the identification of a cAMP-inducible transcriptional repressor that is termed the 'inducible cAMP early repressor'. 36,37 Inducible cAMP early repressor attenuates IL-2 expression by competitively binding to the transcription factor cAMP response element-binding protein.…”

“…10,11 Increasing evidence indicates that Tregs mediate immunosuppressive functions through the utilization of many soluble mediators and cell-to-cell contact, further inducing a positive feedback loop. 1 Bopp et al 12 showed that natural Tregs can transfer cyclic adenosine monophosphate (cAMP) to Teff cells, resulting in increased intracellular cAMP concentrations in Teff cells. 12 Further investigations have shown that phosphodiesterase, which is the enzyme that accelerates the turnover of cAMP, is upregulated in activated Teff cells, improving T cell-based tumor clearance.…”

“…1 Bopp et al 12 showed that natural Tregs can transfer cyclic adenosine monophosphate (cAMP) to Teff cells, resulting in increased intracellular cAMP concentrations in Teff cells. 12 Further investigations have shown that phosphodiesterase, which is the enzyme that accelerates the turnover of cAMP, is upregulated in activated Teff cells, improving T cell-based tumor clearance. [13][14][15][16] Huang et al verified that miR-142-3p restricts cAMP production in Teff cells and Tregs.…”

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

“…Thus, production of adenosine by T regs along with their responsiveness to this metabokine (adenosine) proves detrimental to host suffering from tumor in terms of poor prognosis of tumor. This immunosuppression is mediated by intracellular rise of cAMP levels in both T regs as well as T effs , as T regs are capable of transferring cAMP to T effs via gap junctions [226]. Both these conditions are responsible for the development of more immunosuppressive environment within the tumor microenvironment.…”