Pulmonary exacerbations in early CF lung disease

Background: In chronic cystic fibrosis (CF) lung disease, neutrophilic inflammation and T-cell inhibition occur concomitantly, partly due to neutrophil-mediated release of the T-cell inhibitory enzyme Arg1. However, the onset of this tonic inhibition of T cells, and the impact of pulmonary exacerbations (PEs) on this process remains unknown.
Methods: Children with CF aged 0-5 years were enrolled in a longitudinal cohort study at Emory University. Blood (n = 35) and BAL fluid (n = 18) were collected at stable outpatient clinic visits or inpatient PE hospitalizations and analyzed by flow cytometry (for immune cell presence and phenotype) and 20-plex chemiluminescence assay (for immune mediators). Patients were categorized by PE history into no prior PE, past history of PE prior to stable visit, or current PE.
Results: PEs were associated with increased concentration of both pro- and anti-inflammatory mediators in BAL and increased neutrophil frequency and G-CSF in circulation. PE BAL samples showed a trend for an increased frequency of hyperexocytic GRIM neutrophils previously identified in chronic CF. When comparing the expression of the T-cell receptor associated molecule CD3 and the inhibitory programmed death-1 (PD-1) receptor on T cells from bronchoalveolar lavage (BAL) vs. blood samples, we found that CD3 was significantly decreased and PD-1 expression was increased across the board in all patients. When categorized by PE status, there was no difference in CD3 or PD-1 expression on the circulating blood T cells, but CD3 expression was decreased, and PD-1 was increased on BAL T cells from current PE samples.
Conclusions: These data suggest that airway T cells are engaged during early-life PEs prior to the onset of chronic neutrophilic inflammation. However, increased neutrophil frequency in circulation and trend towards increasing frequency of GRIM neutrophils in the airway offers new insights into the mechanisms of how childhood PEs may accelerate airway inflammation and shift the balance of airway immune cells towards neutrophil dominance.