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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.

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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.