The Journal of Experimental Medicine
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Published online May 14, 2007
doi:10.1084/jem.20062129
The Journal of Experimental Medicine, Vol. 204, No. 6, 1303-1310
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Bopp et al.
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BRIEF DEFINITIVE REPORT

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

Tobias Bopp1, Christian Becker2, Matthias Klein1, Stefan Klein-Heßling4, Alois Palmetshofer4, Edgar Serfling4, Valeska Heib1, Marc Becker1, Jan Kubach2, Steffen Schmitt3, Sabine Stoll2, Hansjörg Schild1, Martin S. Staege5, Michael Stassen1, Helmut Jonuleit2, and Edgar Schmitt1

1 Institute for Immunology, 2 Department of Dermatology, and 3 Center for Natural Sciences and Medicine, Johannes Gutenberg University, 55131 Mainz, Germany
4 Department of Molecular Pathology, Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany
5 Klinik und Poliklinik für Kinder- und Jugendmedizin, Martin Luther University, 06097 Halle-Wittenberg, Germany

CORRESPONDENCE Edgar Schmitt: eschmitt{at}mail.uni-mainz.de

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.


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