Identification of two immune system changes that may contribute to infectious pathology in cystic fibrosis

Cystic fibrosis (CF) affects 80,000 individuals worldwide and is caused by either abnormal or nonfunctional cystic fibrosis transmembrane conductance regulatory (CFTR) protein, which is normally expressed by epithelial cells and lymphocytes and primarily functions as a chloride channel. CFTR deficiency in respiratory epithelial cells has been well studied and results in the accumulation of thick and sticky mucus lining the airways, promoting infection and preventing normal function of the mucociliary escalator and cough clearance. Despite a vigorous immune response in people with CF, chronic respiratory tract infections, particularly with Pseudomonas aeruginosa are the major cause of morbidity and mortality. We have identified two types of changes in the immune systems of people with CF that may contribute to their inability to clear respiratory infections.

PPARγ is an important anti-inflammatory transcriptional regulator. We have demonstrated a reduced level of PPARγ in bronchoalveolar lavage (BAL) cell pellets from children with CF was specifically associated with P. aeruginosa infection rather than with infection in general. We propose this decrease is a consequence of PPARγ antagonism by the major Pseudomonas quorum sensing regulator, 3OC12HSL.

The role of CFTR-deficient lymphocytes in disease pathology is poorly understood yet evidence suggests a systemic hyperinflammatory state exists in CF implying an intrinsic failure to control inflammation. We hypothesised that a primary CFTR-mediated defect in T cells alters their function. Using flow cytometry we identified normal levels of CD4+ T cells in the peripheral blood of people with CF but altered proportions of regulatory CD4 T cell subsets. We found a significantly higher level of FoxP3+ Tregs and IL-10 producing and TGFβ-producing CD4+ T cells in people with CF than in healthy controls and a significant positive correlation between increased levels of TGFβ-producing CD4+ T cells and P. aeruginosa infection.

In conclusion, understanding changes in the immune response of people with CF has the potential to identify new therapeutic targets.