Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression.
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.
Bopp
Tobias
T
Institute for Immunology, Johannes Gutenberg University, 55131 Mainz, Germany.
Becker
Christian
C
Klein
Matthias
M
Klein-Hessling
Stefan
S
Palmetshofer
Alois
A
Serfling
Edgar
E
Heib
Valeska
V
Becker
Marc
M
Kubach
Jan
J
Schmitt
Steffen
S
Stoll
Sabine
S
Schild
Hansjörg
H
Staege
Martin S
MS
Stassen
Michael
M
Jonuleit
Helmut
H
Schmitt
Edgar
E
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017630:Connexins; D000242:Cyclic AMP / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017629:Gap Junctions / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009842:Oligopeptides; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000276:immunology*; D013491:Suppressor Factors, Immunologic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D017630:Connexins; D016207:Cytokines; D017931:DNA Primers; D009842:Oligopeptides; D013491:Suppressor Factors, Immunologic; C455880:gap 27 peptide; D000242:Cyclic AMP