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IL-2 Receptor β-Chain Signaling Controls Immunosuppressive CD4⁺ T Cells in the Draining Lymph Nodes and Lung during Allergic Airway Inflammation In Vivo

Aysefa Doganci^1,*, Roman Karwot^1,*, Joachim H. Maxeiner^1,*, Petra Scholtes^*, Edgar Schmitt, Markus F. Neurath, Hans Anton Lehr, I-Cheng Ho^¶ and Susetta Finotto^2,*

^* Laboratory of Cellular and Molecular Immunology of the Lung, I. Medical Clinic, University of Mainz, Mainz, Germany; Institute of Immunology, University of Mainz, Mainz, Germany; Laboratory of Mucosal Immunology, I. Medical Clinic, Institute of Molecular Medicine, University of Mainz, Mainz, Germany; Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; and ^¶ Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115

IL-2 influences both survival and differentiation of CD4⁺ T effector and regulatory T cells. We studied the effect of i.n. administration of Abs against the - and the β-chains of the IL-2R in a murine model of allergic asthma. Blockade of the β- but not the -chain of the IL-2R after allergen challenge led to a significant reduction of airway hyperresponsiveness. Although both treatments led to reduction of lung inflammation, IL-2 signaling, STAT-5 phosphorylation, and Th2-type cytokine production (IL-4 and IL-5) by lung T cells, IL-13 production and CD4⁺ T cell survival were solely inhibited by the blockade of the IL-2R β-chain. Moreover, local blockade of the common IL-2R/IL-15R β-chain reduced NK cell number and IL-2 production by lung CD4⁺CD25⁺ and CD4⁺CD25^– T cells while inducing IL-10- and TGF-β-producing CD4⁺ T cells in the lung. This cytokine milieu was associated with reduced CD4⁺ T cell proliferation in the draining lymph nodes. Thus, local blockade of the β-chain of the IL-2R restored an immunosuppressive cytokine milieu in the lung that ameliorated both inflammation and airway hyperresponsiveness in experimental allergic asthma. These findings provide novel insights into the functional role of IL-2 signaling in experimental asthma and suggest that blockade of the IL-2R β-chain might be useful for therapy of allergic asthma in humans.

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 A.D., R.K., and J.H.M. contributed equally to this paper.

² Address correspondence and reprint requests to Prof. Susetta Finotto, Laboratory of Cellular and Molecular Lung Immunology, Asthma Core Facility, I. Medical Clinic, University of Mainz, Obere Zahlbacher Strasse 63, Room 2-110, 55010 Mainz, Germany. E-mail address: finotto{at}mail.uni-mainz.de

³ Abbreviations used in this paper: T reg, regulatory T cell; i.n., intranasal(ly); AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; BALF, BAL fluid.