Lack of CFTR in CD3+ Lymphocytes Leads to Aberrant Cytokine Secretion and Hyper-Inflammatory Adaptive Immune Responses: A Master's Thesis
Authors
Mueller, ChristianFaculty Advisor
Katherine Luzuriaga, M.D.Academic Program
Master of Science in Clinical InvestigationUMass Chan Affiliations
Molecular MedicineDocument Type
Master's ThesisPublication Date
2012-04-24Keywords
Cystic Fibrosis Transmembrane Conductance RegulatorCytokines
Lymphocytes
Mutation
Antigens
CD3
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Biological Factors
Cells
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Digestive System Diseases
Hemic and Immune Systems
Immunology and Infectious Disease
Life Sciences
Medicine and Health Sciences
Respiratory Tract Diseases
Metadata
Show full item recordAbstract
Background: Cystic fibrosis (CF) remains the most common fatal monogenic disease in the US, affecting 1 in 3,300 live births. CF is the result of mutations in CFTR, a chloride channel and regulator of other ion channels. The mechanisms by which CFTR mutations cause chronic lung disease in CF are not fully defined, but may include the combined effects of 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) when compared to Cftr+/+ mice. Along with the increased IgE levels, the Cftr-/- mice had higher levels of IL-13 and IL-4, mimicking both the Th-2 biased immune responses and predilection to mounting Af-specifc IgE seen in CF patients. Herein we hypothesize that these immune aberrations are primarily due to the lack of Cftr expression in lymphocytes rather than with Cftr deficiency in the epithelium. Results: Our results indicate that adoptive transfer experiments with Cf splenocytes confer higher IgE response to Af in host mice as compared to hosts receiving wild-type splenocytes. The predilection of Cftr-deficient lymphocytes to mount Th2 responses was confirmed by in vitro antigen recall experiments, where higher levels of IL-13 and IL-4 where seen only in the presence of Cftr-deficient lymphocytes. Conclusive data on this phenomenon were obtained with conditional Cftr knockout mice, where mice lacking Cftr in T-cell lineages developed the higher IgE titers as compared to their wild-type littermate controls. Further analysis of Cftr-deficient lymphocytes revealed an enhanced intracellular Ca 2+ flux in response to T cell receptor activation as compared to normal lymphocytes. This was accompanied by a significant increase in nuclear localization of the calcium-sensitive transcription factor NFAT, which could contribute to the enhanced secretion of IL-13 and other cytokines. Conclusions: In summary, our data identified that CFTR dysfunction in T cells can lead directly to aberrant immune responses. This is the first instance that a CF related phenotype has been entirely modeled in vivo by selectively knocking out CFTR in the immune system. Specifically, Cftr deficient lymphocytes directed skewed responses to Aspergillus fumigatus , leading to a higher than normal IgE response. These findings implicate the lymphocyte population as a potentially important target for therapeutics directed to the treatment of CF lung disease.DOI
10.13028/jwfz-5d15Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31940Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/jwfz-5d15