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Aspergillus fumigatus Generates an Enhanced Th2-Biased Immune Response in Mice with Defective Cystic Fibrosis Transmembrane Conductance Regulator¹

Jenna B. Allard^*, Matthew E. Poynter^*, Kieren A. Marr, Lauren Cohn, Mercedes Rincon and Laurie A. Whittaker^2,*

^* Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405; Program in Infectious Disease, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA 98109; Division of Pulmonary and Critical Care Medicine, Yale University, New Haven, CT 06510; and Division of Immunobiology, Department of Medicine, University of Vermont, Burlington, VT 05405

Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20–40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftr^tm1Unc-TgN(fatty acid-binding protein)CFTR) and mutant (F508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4⁺ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4⁺ T cells. The Th2 bias of CD4⁺ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4⁺ T cells.

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 Center for Biomedical Research Excellence Program of the National Center for Research Resources Grant P20RR15557, the Cystic Fibrosis Foundation and a Biomedical Research Infrastructure Network award from the National Center for Research Resources, and National Institutes of Health Grant RO1 AI 51468 (to K.A.M.).

² Address correspondence and reprint requests to Dr. Laurie A. Whittaker, Health Science Research Facility, Room 222, University of Vermont, 149 Beaumont Avenue, Burlington, VT 05405. E-mail address: laurie.whittaker{at}uvm.edu

³ Abbreviations used in this paper: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; ABPA, allergic bronchopulmonary aspergillosis; AHA, A. fumigatus hyphal Ag; KO, knockout; WT, wild type; alum, aluminum hydroxide; BAL, bronchoalveolar lavage; HPRT, hypoxanthine phosphoribosyltransferase; C_T, threshold cycle.

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