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Activin A Promotes the TGF-β-Induced Conversion of CD4⁺CD25^– T Cells into Foxp3⁺ Induced Regulatory T Cells ¹

Samuel Huber^*, Felix R. Stahl^*, Jörg Schrader^*, Stefan Lüth^*, Katrin Presser^*, Antonella Carambia^*, Richard A. Flavell, Sabine Werner, Manfred Blessing, Johannes Herkel^* and Christoph Schramm^2,*

^* I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Institut für Zellbiologie, Departement Biologie, Eidgenössische Technische Hochschule, Zürich; Switzerland; and Biotechnologisches Biomedizinisches Zentrum, Universität Leipzig, Leipzig, Germany

TGF-β induces the conversion of CD4⁺CD25^– T cells into CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg). Activin A is a pleiotropic TGF-β family member and is expressed in response to inflammatory signals. In this study, we report on the effects of activin A on the conversion of CD4⁺CD25^– T cells into Foxp3-expressing induced Treg (iTreg). Activin A was able to promote the conversion of CD4⁺CD25^– T cells into iTreg in a dose-dependent manner in vitro. Activin A together with TGF-β1 had synergistic effects on the rate of iTreg conversion in vitro. Intact TGF-β1 signaling seemed to be essential for the effects of activin A on iTreg generation because cells overexpressing a dominant negative TGF-β type II receptor could not be converted by activin A in vitro. In vivo, the frequency of peripheral, but not central, Treg was increased in transgenic mice with elevated activin A serum levels and the in vivo conversion rate of CD4⁺CD25^– T cells into Foxp3-expressing iTreg was increased as compared with wild type mice. These data suggest a role for activin A as a promoter of the TGF-β dependent conversion of CD4⁺CD25^– T cells into iTreg in vitro and in vivo. Therefore, besides promoting inflammation, activin A may contribute to the regulation of inflammation via the expansion of peripheral Treg.

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 Deutsche Forschungsgemeinschaft (SCHR 781/1-2, 781/2-1, HU 1714/1-1), Werner Otto Stiftung, Novartis Research Foundation, and by the University Medical Center Hamburg-Eppendorf (NWF-07/04).

² Address correspondence and reprint requests to Dr. C. Schramm, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail address: cschramm{at}uke.de

³ Abbreviations used in this paper: Treg, regulatory T cell; iTreg, induced Treg.

⁴ The online version of this article contains supplemental material.

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The JI 2009 182: 4493-4494. [Full Text]  

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