CFTR negatively reprograms Th2 cell responses, and CFTR potentiation restrains allergic airway inflammation
Mark Rusznak, … , R. Stokes Peebles Jr., Daniel P. Cook
Mark Rusznak, … , R. Stokes Peebles Jr., Daniel P. Cook
Published March 25, 2025
Citation Information: JCI Insight. 2025;10(9):e191098. https://doi.org/10.1172/jci.insight.191098.
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Research Article Immunology Inflammation Pulmonology

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

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.

Authors

Mark Rusznak, Christopher M. Thomas, Jian Zhang, Shinji Toki, Weisong Zhou, Masako Abney, Danielle M. Yanda, Allison E. Norlander, Craig A. Hodges, Dawn C. Newcomb, Mark H. Kaplan, R. Stokes Peebles Jr., Daniel P. Cook

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Figure 5

CFTR deficiency enhances IL-4 sensitivity and GATA3 expression in Th2 cells.

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CFTR deficiency enhances IL-4 sensitivity and GATA3 expression in Th2 ce...
(A) Schematic diagram showing isolation and polarization conditions of naive CD4+ T cells to Th2 cells for IL-4 studies. (B) Representative flow cytometry histogram showing the median fluorescence intensity (MFI) of IL-4Rα at 72 hours for Cftr+/+ and Cftr−/− Th2 cells. (C) The quantified MFI of IL-4Rα in Cftr+/+ and Cftr−/− Th2 cells at 72 hours (n = 5 mice per genotype). (D) Representative flow cytometry histogram showing the MFI of GATA3 at 72 hours for Cftr+/+ and Cftr−/− Th2 cells. (E) The quantified MFI of GATA3 in Cftr+/+ and Cftr−/− Th2 cells at 72 hours (n = 5 mice per genotype). (F) Representative CD4+ populations showing the MFI of GATA3 at 72 hours in the presence of increasing doses of polarizing IL-4 (0–40 ng/mL) for Cftr+/+ and Cftr−/− Th2 cells. (G and H) GATA3 MFI and secreted IL-13 from cellular supernatant in cultured Cftr+/+ (black) and Cftr−/− (red) Th2 cells in the presence of increasing doses of IL-4 (0–40 ng/mL). (C and E) Data are shown as mean ± SD. Statistical analysis in C and E were performed using unpaired Student’s t test and, in G and H, by 4-parameter logistic regression algorithm (sigmoidal curve fit) to fit. For G and H, data are shown as mean values with the accompanying curve fit (solid line), the 95% CI displayed as a band as well as mean data points for each genotype and concentration. **P < 0.01 and ****P < 0.0001.