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Cutting Edge: Trans-Signaling via the Soluble IL-6R Abrogates the Induction of FoxP3 in Naive CD4⁺CD25^– T Cells¹

Sabine Dominitzki^2,*, Massimo C. Fantini^2,, Clemens Neufert^*, Alexei Nikolaev^*, Peter R. Galle^*, Jürgen Scheller, Giovanni Monteleone, Stefan Rose-John, Markus F. Neurath^3,* and Christoph Becker^3,4,*

^* Laboratory of Immunology, Medical Clinic I, University of Mainz, Mainz, Germany; Department of Internal Medicine, University of Rome "Tor Vergata", Rome, Italy; and Department of Biochemistry, University of Kiel, Kiel, Germany

Chronic inflammatory diseases may develop when regulatory T cells (Tregs) fail to control the balance between tolerance and immunity. Alternatively, activated immune cells might prevent the induction or activation of Tregs in such diseases. In this study, we demonstrate that trans-signaling into T cells via the soluble IL-6 receptor completely abrogates the de novo induction of adaptive Tregs. Mechanistically, IL-6 trans-signaling augmented the expression of the TGF- signaling inhibitor SMAD7. Consequently, SMAD7 overexpression in T cells using newly created transgenic mice rendered CD4⁺CD25^– T cells resistant to the induction of FoxP3. Finally, IL-6 trans-signaling inhibited Treg-mediated suppression in a murine model of colitis. In summary, IL-6 trans-signaling into T cells emerges as a key pathway for blockade of the development of adaptive Tregs and thus may play a pivotal role in shifting the balance between effector and regulatory T cell numbers in chronic inflammatory and autoimmune diseases.

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 work was supported by the collaborative research grant SFB548 from the Deutsche Forschungsgemeinschaft (to C.B. and M.F.N.).

² S.D. and M.C.F. share first authorship.

³ M.F.N. and C.B. share senior authorship.

⁴ Address correspondence and reprint requests to Dr. Christoph Becker, Laboratory of Immunology, Medical Clinic I, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany. E-mail address: chbecker{at}uni-mainz.de

⁵ Abbreviations used in this paper: Treg, regulatory T cell; HA, hemagglutinin; HA-TCRtg/RAG, transgenic for HA-specific TCR (mice); HIL-6, Hyper-IL-6; HPRT, hypoxanthine phosphoribosyltransferase; iTreg, induced Treg; sIL-6R, soluble IL-6R.

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