title: 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.
authors.affiliation: Institute for Immunology, Johannes Gutenberg University, 55131 Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein-Hessling
authors.forename: Alois
authors.initials: A
authors.lastname: Palmetshofer
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
authors.forename: Valeska
authors.initials: V
authors.lastname: Heib
authors.forename: Marc
authors.initials: M
authors.lastname: Becker
authors.forename: Jan
authors.initials: J
authors.lastname: Kubach
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitt
authors.forename: Sabine
authors.initials: S
authors.lastname: Stoll
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.forename: Martin S
authors.initials: MS
authors.lastname: Staege
authors.forename: Michael
authors.initials: M
authors.lastname: Stassen
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
mesh_terms: 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*
chemical_list: D017630:Connexins; D016207:Cytokines; D017931:DNA Primers; D009842:Oligopeptides; D013491:Suppressor Factors, Immunologic; C455880:gap 27 peptide; D000242:Cyclic AMP