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

Authors:
Bopp T, Becker C, Klein M, Klein-Heßling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, Schmitt E
In:
Source: J Exp Med
Publication Date: (2007)
Issue: 204(6): 1303-1310
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
T cell, human stim.
Species: human
Tissue Origin: blood
T cell, mouse - BALB/c
Species: mouse
Tissue Origin: blood
T cell, mouse - C57BL/6
Species: mouse
Tissue Origin: blood
Platform:
Nucleofector™ I/II/2b
Experiment
2x10^6 T-cells (reg) were transfected with 240 µM Alexa Fluor 488 cAMP.
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.