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Ivacaftor Restrains Th2 Cell Development Through a CFTR/IL-4/GATA3 Axis and Reduces Alternaria-induced Allergic Airway Inflammation
Abstract   Peer reviewed

Ivacaftor Restrains Th2 Cell Development Through a CFTR/IL-4/GATA3 Axis and Reduces Alternaria-induced Allergic Airway Inflammation

D.P Cook, C Thomas, M Rusznak, J Zhang, S Toki, W Zhou, M Abney, D Yanda, A Norlander, C Hodges, …
American journal of respiratory and critical care medicine, Vol.211(Supplement_1), pp.A7362-A7362
05/01/2025
DOI: 10.1164/ajrccm.2025.211.Abstracts.A7362

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Abstract

RATIONALE: Type 2 inflammatory diseases such as asthma, sinusitis, and allergic bronchopulmonary aspergillosis are prevalent in Cystic Fibrosis compared to the general population. CD4+ T helper 2 (Th2) cells contribute to these conditions by releasing cytokines like IL-4, IL-5, and IL-13. While recent studies suggest heightened type 2 immune responses occur in CF patients, it remains unclear whether the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF, directly influences Th2 cell development. METHODS: We utilized murine models with CFTR deficiency and human CD4+ T cells to investigate the role of CFTR in Th2 cells. Mice were sensitized and challenged with Alternaria alternata extract to generate allergic inflammation to study the functional consequence of CFTR loss in T cells and therapeutic potential of CFTR potentiation. RESULTS: We found that activated CD4+ T cells expressed both the Cftr transcript and CFTR protein. When CFTR expression was lost in murine T cells, these cells produced higher levels of Th2 cytokines compared to control cells. To study the in vivo effects of CFTR on Th2 mediated allergic inflammation, we created a mouse T cell-specific Cftr knockout model by crossing Cftrfl/fl mice to CD4Cre+ mice, specifically deleting CFTR during T cell thymic development. Mice with CFTR-deficient T cells exhibited more severe allergic airway disease in response to Alternaria extract than control CFTR sufficient mice. To assess the mechanism of CFTR negative regulation on Th2 effector function, we performed bulk RNA sequencing from Cftr+/+ and Cftr-/- Th2 cells. Genes and pathways related to IL-4 and GATA3 signaling were significantly upregulated in Cftr-/- compared to Cftr+/+ Th2 cells. Validating these findings, cultured murine Th2 cells demonstrated increased expression of IL-4Rα and heightened sensitivity to IL-4, resulting in greater production of GATA3 and IL-13 compared to control Th2 cells. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine levels in bronchoalveolar lavage fluid from “humanized” CFTR mice after exposure to Alternaria extract. To assess the translatability of these findings, cultured human primary CD4+ T cells were treated with ivacaftor or DMSO (control). CFTR potentiation with ivacaftor significantly decreased Th2 cell development with significant reductions in intracellular GATA3 and IL-13 expression. CONCLUSION: Collectively, these findings demonstrate that CFTR plays a direct role in modulating T cell sensitivity to IL-4, reducing the IL-4/GATA3 signaling axis and restraining Th2 development. The CFTR potentiator ivacaftor represents a new class of therapies to be repurposed for allergic disease.
 Cystic Fibrosis Cytokines Inflammation Lymphocytes

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