Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses
Authors
Mueller, ChristianBraag, Sofia A.
Keeler, Allison M.
Hodges, Craig
Drumm, Mitchell
Flotte, Terence R.
Document Type
Journal ArticlePublication Date
2011-06-01Keywords
AnimalsAntigens, CD3
Aspergillus
Calcium
Cystic Fibrosis Transmembrane Conductance Regulator
Cytokines
Hypersensitivity
Immune System
Immunoglobulin E
Lymphocytes
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mutation
NFATC Transcription Factors
Spleen
cystic fibrosis transmembrane conductance regulator
lym-phocytes
allergy
intracellular calcium
nuclear factor of activated T cell
Allergy and Immunology
Amino Acids, Peptides, and Proteins
Animal Experimentation and Research
Biological Factors
Cells
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Digestive System Diseases
Hemic and Immune Systems
Investigative Techniques
Medical Genetics
Pediatrics
Respiratory Tract Diseases
Therapeutics
Metadata
Show full item recordAbstract
Cystic fibrosis (CF), the most common fatal monogenic disease in the United States, results from mutations in CF transmembrane conductance regulator (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 toward Aspergillus fumigatus, with higher levels of IL-13 and IL-4, mimicking both the T helper cell type 2-biased immune responses seen in patients with CF. Herein, we demonstrate that these aberrations are primarily due to Cftr deficiency in lymphocytes rather than in the epithelium. Adoptive transfer experiments with CF splenocytes confer a higher IgE response to Aspergillus fumigatus compared with hosts receiving wild-type splenocytes. The predilection of Cftr-deficient lymphocytes to mount T helper cell type 2 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 control littermates. Further analysis of Cftr-deficient lymphocytes revealed an enhanced intracellular Ca(2+) flux in response to T cell receptor activation. This was accompanied by an increase in nuclear localization of the calcium-sensitive transcription factor, nuclear factor of activated T cell, 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.Source
Am J Respir Cell Mol Biol. 2011 Jun;44(6):922-9. Epub 2010 Aug 19.
DOI
10.1165/rcmb.2010-0224OCPermanent Link to this Item
http://hdl.handle.net/20.500.14038/43844PubMed ID
20724552Related Resources
ae974a485f413a2113503eed53cd6c53
10.1165/rcmb.2010-0224OC