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J Immunol. 2012 Feb 1;188(3):1091-7. doi: 10.4049/jimmunol.1102045. Epub 2011 Dec 21.

Repression of cyclic adenosine monophosphate upregulation disarms and expands human regulatory T cells.

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University Medical Center, Institute for Immunology, Johannes Gutenberg-University, 55131 Mainz, Germany.


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.

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