CFTR deficiency increases Th2 cytokine production and allergic airway inflammation in mice

The adaptive immune system is increasingly appreciated for contributions to the exuberant and maladaptive immune response in Cystic Fibrosis (CF). We hypothesized that 1) CFTR-deficiency in mouse Th2 cells increases Th2 cytokine production, 2) CF mice have increased allergic inflammation when challenged with inhaled allergen, and 3) GATA-3 expression is increased in murine CFTR-deficient Th2 cells. Naïve CD4+ T cells from Wild type (WT) and CFTR knockout mice (CF) were isolated and polarized to Th2 cells. Comparative whole transcriptomic analysis from Th2 cells was performed. Both WT and CF mice were sensitized and challenged using Alternaria extract to elicit an adaptive immune response. Bronchoalveolar lavage (BAL), whole lung homogenate, and histopathological analysis was performed. In WT T cells, CFTR expression is tightly associated with T cell activation. Th2 cells from CF mice produce higher levels of IL-4, IL-5, and IL-13 in response to activation compared to WT Th2 cells. Following activation and polarization, CFTR deficiency in Th2 cells leads to upregulation of 136 genes and downregulation of 56 genes. Comparative analysis revealed increase in GATA-3 expression in CFTR-deficient T cells. In vivo, CF mice display increased inflammation by histology and increased Th2 cytokine production in response to Alternaria challenge compared to WT mice. These findings demonstrate a role for CFTR in lymphocyte function and allergic inflammation. CFTR modulator therapies for CF could decrease allergic inflammation in patients with CF.