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¹ Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
² Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London EC2A 2DB, England, UK
³ Allergy and Clinical Immunology Section and ⁴ Leukocyte Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London SW7 2AZ, England, UK

CORRESPONDENCE Georgina Xanthou: gxanthou{at}bioacademy.gr

Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell–mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor β1 reverses activin-A–induced suppression. Remarkably, transfer of activin-A–induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease.

V. Panoutsakopoulou and G. Xanthou contributed equally to this paper.

Abbreviations used: Act-RIIA, activin receptor type IIA; AHR, airway hyperresponsiveness; ALK, activin-like kinase; alum, aluminum hydroxide; BAL, bronchoalveolar lavage; DLN, draining LN; EAE, experimental autoimmune encephalomyelitis; FEV₁, forced expiratory volume in 1 s; Foxp3, forkhead box p3; H&E, hematoxylin and eosin; PAS, periodic acid–Schiff; PenH, enhanced pause; r-activin-A, recombinant activin-A.

© 2009 Semitekolou et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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