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Inhibition of cAMP Degradation Improves Regulatory T Cell-Mediated Suppression¹

Tobias Bopp^2,*, Nina Dehzad^2,, Sebastian Reuter, Matthias Klein^*, Nina Ullrich^*, Michael Stassen^*, Hansjörg Schild^*, Roland Buhl, Edgar Schmitt^3,* and Christian Taube

^* Institute for Immunology, Department of Pulmonary Medicine, III. Medical Clinic, Johannes Gutenberg-University, Mainz, Germany

Naturally occurring regulatory T cells (nTreg cells) are crucial for the maintenance of peripheral tolerance. We have previously shown that a key mechanism of their suppressive action is based on a contact-dependent transfer of cAMP from nTreg cells to responder T cells. Herein, we further elucidate the important role of cAMP for the suppressive properties of nTreg cells. Prevention of cAMP degradation by application of the phosphodiesterase 4 inhibitor rolipram led to strongly increased suppressive potency of nTreg cells for Th2 cells in vitro and in vivo. Detailed analyses revealed that rolipram caused, in the presence of nTreg cells, a synergistic increase of cAMP in responder Th2 cells. In vivo, the application of nTreg cells in a strictly Th2-dependent preclinical model of asthma had only a marginal effect. However, the additional treatment with rolipram led to a considerable reduction of airway hyperresponsiveness and inflammation in a prophylactic as well as in a therapeutic model. This amelioration was correlated with enhanced cAMP-levels in lung Th2 cells in vivo. Collectively, these data support our observation that cAMP has a key function for nTreg cell-based suppression and they clearly demonstrate that the effect of cAMP on T responder cells can be greatly enhanced upon application of phosphodiesterase 4 inhibitors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was funded by Deutsche Forschungsgemeinschaft, TR52 TPA1 (to T.B. and E.S.), SFB 548 A6 (to T.B. and E.S.), A10 (to M.S.), and A11 (to C.T.), the Carl Zeiss Foundation, and the Mainzer Forschungsförderungsprogramm des Fachbereichs Medizin (MAIFOR).

² T.B. and N.D. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Edgar Schmitt, Institute of Immunology, Obere Zahlbacherstr. 67, Mainz, Germany. E-mail address: eschmitt{at}mail.uni-mainz.de

⁴ Abbreviations used in this paper: AHR, airway hyperresponsiveness; Treg, regulatory T cell; nTreg, naturally occurring Treg cell; iTreg, induced Treg cell; PDE, phosphodiesterase; BAL, bronchoalveolar lavage; R_L, airway resistance; C_dyn, dynamic compliance; MCh, methacholine; PAS, periodic acid-Schiff; preTreg, preactivated nTreg; TCC, total cell count.

⁵ The online version of this article contains supplemental material.