Aspergillus fumigatus generates an enhanced Th2-biased immune response in mice with defective cystic fibrosis transmembrane conductance regulator.
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 (DeltaF508) 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.
Allard
Jenna B
JB
Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
Poynter
Matthew E
ME
Marr
Kieren A
KA
Cohn
Lauren
L
Rincon
Mercedes
M
Whittaker
Laurie A
LA
D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology; D007109:Immunity; D007249:Inflammation; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology*
D000946:Antigens, Fungal; D019005:Cystic Fibrosis Transmembrane Conductance Regulator