Journal article
CFTR negatively reprograms Th2 cell responses and CFTR potentiation restrains allergic airway inflammation
JCI insight, Vol.10(9), e191098
05/08/2025
DOI: 10.1172/jci.insight.191098
PMCID: PMC12128969
PMID: 40131363
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.
Details
- Title: Subtitle
- CFTR negatively reprograms Th2 cell responses and CFTR potentiation restrains allergic airway inflammation
- Creators
- Mark Rusznak - Vanderbilt University Medical CenterChristopher M Thomas - Vanderbilt University Medical CenterJian Zhang - Vanderbilt University Medical CenterShinji Toki - Vanderbilt University Medical CenterWeisong Zhou - Vanderbilt University Medical CenterMasako Abney - Vanderbilt University Medical CenterDanielle M Yanda - University of IowaAllison E Norlander - Indiana University – Purdue University IndianapolisCraig A Hodges - Case Western Reserve UniversityDawn C Newcomb - Vanderbilt University Medical CenterMark H Kaplan - Indiana University – Purdue University IndianapolisR Stokes Peebles Jr - Vanderbilt UniversityDaniel P Cook - Vanderbilt University Medical Center
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.10(9), e191098
- DOI
- 10.1172/jci.insight.191098
- PMID
- 40131363
- PMCID
- PMC12128969
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- National Institute of Allergy and Infectious Diseases: F30AI176712, K08AI181763, R01AI124456, R01AI145265, U19AI095227, R01AI111820, R21AI145397 United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Service: 101BX004299 Cystic Fibrosis Foundation: COOK20L0, COOK24A0-KB, COOK25R3, HODGES19R1
We thank D. Stoltz from the University of Iowa for his assistance in experimental design. We appreciate the input of J. Tolle and the CF clinic at Vanderbilt University Medical Center. This work was supported by grants from the National Institute of Allergy and Infectious Diseases (F30AI176712 to MR, K08AI181763 to DPC, and R01AI124456, R01AI145265, U19AI095227, R01AI111820, and R21AI145397 to RSP) , the United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Service (101BX004299 to RSP) , and the Cystic Fibrosis Foundation (COOK20L0, COOK24A0-KB, and COOK25R3 to DPC, and HODGES19R1 to CAH) .
- Language
- English
- Electronic publication date
- 03/25/2025
- Date published
- 05/08/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984802411202771
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