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

By T. Bopp, C. Becker, M. Klein, S. Klein-Hessling, A. Palmetshofer, E. Serfling, V. Heib, M. Becker, J. Kubach, S. Schmitt and 6 more. Journal of Experimental Medicine, 2007

704 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/36a8803505bbfd03fe133edd1633501370aef8de

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In Epidemiology

1. Shimon Sakaguchi
2. Y. Belkaid

In Immunology

1. Shimon Sakaguchi
2. K. Wing
3. J. Bluestone
4. Tomoyuki Yamaguchi
5. Q. Tang
6. D. Vignali
7. C. Workman
8. L. Collison

Citations in the corpus

• How regulatory T cells work (2008, background): “T Reg cells were also shown to suppress effector T-cell function directly by transferring the potent inhibitory second messenger cyclic AMP (cAMP) into effector T cells through membrane gap junction”
• Regulatory T cells and infection: a dangerous necessity (2007, background): “More recently, adenosine and cyclic AMP have also been shown to contribute to T Reg -cell suppressive activit”
• The Foxp3+ regulatory T cell: a jack of all trades, master of regulation (2008, background): “A mechanism to explain the contact dependence of in vitro suppression has been proposed in a publication showing that T reg cells have large amounts of cytoplamic cAMP and could deliver this potent immunosuppressive compound to T eff cells by contact through gap junction”
• Regulatory T cells: how do they suppress immune responses? (2009, background): “Following cell contact, Tregs may kill responder T cells by a granzyme-dependent or perforin-dependent mechanism (17, 18) or deliver a negative signal to responder T cells via (i) up-regulating intracellular cyclic AMP, which leads to inhibition of T cell proliferation and IL-2 formation ( 19 ); (ii”