title: Repression of cyclic adenosine monophosphate upregulation disarms and expands human regulatory T cells.
abstract: The main molecular mechanism of human regulatory T cell (Treg)-mediated suppression has not been elucidated. We show in this study that cAMP represents a key regulator of human Treg function. Repression of cAMP production by inhibition of adenylate cyclase activity or augmentation of cAMP degradation through ectopic expression of a cAMP-degrading phosphodiesterase greatly reduces the suppressive activity of human Treg in vitro and in a humanized mouse model in vivo. Notably, cAMP repression additionally abrogates the anergic state of human Treg, accompanied by nuclear translocation of NFATc1 and induction of its short isoform NFATc1/αA. Treg expanded under cAMP repression, however, do not convert into effector T cells and regain their anergic state and suppressive activity upon proliferation. Together, these findings reveal the cAMP pathway as an attractive target for clinical intervention with Treg function.
authors.affiliation: University Medical Center, Institute for Immunology, Johannes Gutenberg-University, 55131 Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.forename: Martin
authors.initials: M
authors.lastname: Vaeth
authors.forename: Tobias
authors.initials: T
authors.lastname: Scheel
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Friederike
authors.initials: F
authors.lastname: Berberich-Siebelt
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D017635:Clonal Anergy; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D000242:Cyclic AMP