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Regulation of the foxp3 Gene by the Th1 Cytokines: The Role of IL-27-Induced STAT1¹

Nadia Ouaked^*, Pierre-Yves Mantel^*,, Claudio Bassin^*, Simone Burgler^*, Kerstin Siegmund^*, Cezmi A. Akdis^* and Carsten B. Schmidt-Weber^2,

^* Swiss Institute of Allergy and Asthma Research Davos, affiliated with the University of Zurich, Davos-Platz, Switzerland; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and Allergy and Clinical Immunology, National Heart & Lung Institute, Imperial College, London, United Kingdom

Impaired functional activity of T regulatory cells has been reported in allergic patients and results in an increased susceptibility to autoimmune diseases. The master regulator of T regulatory cell differentiation, the transcription factor FOXP3, is required for both their development and function. Despite its key role, relatively little is known about the molecular mechanisms regulating foxp3 gene expression. In the present study, the effect of Th1 cytokines on human T regulatory cell differentiation was analyzed at epigenetic and gene expression levels and reveals a mechanism by which the STAT1-activating cytokines IL-27 and IFN- amplify TGF-β-induced FOXP3 expression. This study shows STAT1 binding elements within the proximal part of the human FOXP3 promoter, which we previously hypothesized to function as a key regulatory unit. Direct binding of STAT1 to the FOXP3 promoter following IL-27 stimulation increases its transactivation process and induces permissive histone modifications in this key region of the FOXP3 promoter, suggesting that FOXP3 expression is promoted by IL-27 by two mechanisms. Our data demonstrate a molecular mechanism regulating FOXP3 expression, which is of considerable interest for the development of new drug targets aiming to support anti-inflammatory mechanisms of the immune system.

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 in part by a scholarship from the Institut de Recherche Robert-Sauvé en Santé et Sécurité au Travail (to N.O.) and Swiss National Science Foundation Grant SNF 310000-112329 (to C.B.S.W.).

N.O., P.-Y.M., C.A.A., and C.B.S.-W. conceived and designed the experiments. N.O. and P.-Y.M. performed the experiments. N.O., P.-Y.M., C.B., S.B., K.S., C.A.A., and C.B.S.W. analyzed the data. N.O., P.-Y.M., C.B., C.A.A., and C.B.S.-W. contributed reagents/materials/analysis tools. N.O., C.A.A., and C.B.S.-W. wrote the article.

² Address correspondence and reprint requests to Dr. Carsten B. Schmidt-Weber, Allergy and Clinical Immunology, National Heart & Lung Institute, Imperial College, Sir Alexander Flemming Building, Room 365, Exhibition Road, London SW7 2AZ, U.K. E-mail address: c.schmidt-weber{at}imperial.ac.uk

³ Abbreviations used in this paper: GATA-3, GATA-binding protein 3; ChIP, chromatin immune precipitation; FOXP3, human forkhead box p3; Foxp3, mice forkhead box p3; T_reg, T regulatory; iT_reg, inducible T_reg; TSS, transcription start site.

⁴ The online version of this article contains supplemental material.