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

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

doi:10.1172/jci.insight.191098

Published March 25, 2025 - More info

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Abstract

Type 2 inflammatory diseases are common in cystic fibrosis (CF) including asthma, sinusitis, and allergic bronchopulmonary aspergillosis. CD4⁺ T helper 2 (Th2) cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the cystic fibrosis 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 CD4⁺ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared to control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared to 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 to 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. Together, 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.

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

Mark Rusznak,¹ Christopher M. Thomas,¹ Jian Zhang,¹ Shinji Toki,¹ Weisong Zhou,¹ Masako Abney,¹ Danielle M. Yanda,² Allison E. Norlander,³ Craig A. Hodges,⁴ Dawn C. Newcomb,¹ Mark H. Kaplan,⁵ R. Stokes Peebles Jr.,¹ and Daniel P. Cook¹

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

Mark Rusznak,1 Christopher M. Thomas,1 Jian Zhang,1 Shinji Toki,1 Weisong Zhou,1 Masako Abney,1 Danielle M. Yanda,2 Allison E. Norlander,3 Craig A. Hodges,4 Dawn C. Newcomb,1 Mark H. Kaplan,5 R. Stokes Peebles Jr.,1 and Daniel P. Cook1

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Mark Rusznak,¹ Christopher M. Thomas,¹ Jian Zhang,¹ Shinji Toki,¹ Weisong Zhou,¹ Masako Abney,¹ Danielle M. Yanda,² Allison E. Norlander,³ Craig A. Hodges,⁴ Dawn C. Newcomb,¹ Mark H. Kaplan,⁵ R. Stokes Peebles Jr.,¹ and Daniel P. Cook¹