Gene Therapy Center; Department of Pediatrics
Medical Subject Headings
Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; T-Lymphocytes; Adaptive Immunity; NFATC Transcription Factors
Immunity | Respiratory Tract Diseases
Cystic fibrosis (CF), the most common fatal monogenic disease in the US, results from mutations in CFTR, a chloride channel. The mechanisms by which CFTR mutations cause lung disease in CF are not fully defined, but may include altered ion and water transport across the airway epithelium and aberrant inflammatory and immune responses to pathogens within the airways. We have shown that Cftr-/- mice mount an exaggerated IgE response towards Aspergillus fumigatus (Af) with higher levels of IL-13 and IL-4, mimicking both the Th-2 biased immune responses seen in CF patients. Herein, we demonstrated that these aberrations are primarily due to Cftr deficiency in lymphocytes rather than in the epithelium. Adoptive transfer experiments with Cf splenocytes confer higher IgE response to Af as compared to hosts receiving wild-type splenocytes. The predilection of Cftr-deficient lymphocytes to mount Th2 responses with high IL-13 and IL-4 was confirmed by in vitro antigen recall experiments. Conclusive data on this phenomenon were obtained with conditional Cftr knockout mice, where mice lacking Cftr in T-cell lineages developed higher IgE than their wild-type littermate controls. Further analysis of Cftr-deficient lymphocytes revealed an enhanced intracellular Ca2+ flux in response to T cell receptor activation. This was accompanied by an increase in nuclear localization of the calcium-sensitive transcription factor NFAT, which could drive the IL-13 response. In summary, our data identified that CFTR dysfunction in T cells can lead directly to aberrant immune responses. These findings implicate the lymphocyte population as a potentially important target for CF therapeutics.
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Citation: Am. J. Respir. Cell Mol. Biol. 2010, doi:10.1165/rcmb.2010-0224OC.