CFTR negatively reprograms Th2 cell responses, and CFTR potentiation restrains allergic airway inflammation

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2025-03-25
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American English
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American Society for Clinical Investigation
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Abstract

Type 2 inflammatory diseases, including asthma, sinusitis, and allergic bronchopulmonary aspergillosis, are common in cystic fibrosis (CF). CD4+ Th2 cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the CF transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show that CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared with control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared with control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared with control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of humanized CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. These data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.

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Rusznak M, Thomas CM, Zhang J, et al. CFTR negatively reprograms Th2 cell responses, and CFTR potentiation restrains allergic airway inflammation. JCI Insight. 2025;10(9):e191098. Published 2025 Mar 25. doi:10.1172/jci.insight.191098
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