CFTR function of dendritic cells reveals a novel mechanism of inflammation in the cystic fibrosis lung

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Airway inflammation is a common feature of cystic fibrosis (CF) lung disease. Major histocompatibility complex class II (MHCII) molecules expressed on dendritic cells (DCs) play a pivotal role in presenting bacterial antigens to T lymphocytes to trigger the immune response. We show here that the cystic fibrosis transmembrane regulator (CFTR) is expressed in DCs where it participates in regulating plasma membrane MHCII expression. DCs from CFTR−/− mice showed enhanced plasma membrane expression of MHCII as well as stimulatory effect on CD4+ T cell proliferation. Metabolic labeling studies showed that degradation of invariant chain (Ii) in MHCII‐Ii complex was significantly greater in DCs from CFTR−/− mice than CFTR+/+ mice. Lysosomal acidification in DCs from CFTR−/− mice was also greater and acidification was prevented by amiloride, an epithelial sodium channel (ENaC) inhibitor. Thus, CFTR may regulate MHCII plasma membrane expression and antigen presentation by inhibiting lysosomal ENaC, and thus modulate lysosomal acidification. These results suggest a novel pathogenic mechanism of inflammation in cystic fibrosis patients based on the hyper‐activation of the immune response. This work was supported by Parker B. Francis Fellowships in Pulmonary Research and US National Institutes of Health grants P01 HL77806.