Th17/Treg Imbalance in Murine Cystic Fibrosis is Linked to IDO Deficiency but Corrected by Kynurenines.

Abstract RATIONALE: Mutations in cystic fibrosis (CF) transmembrane conductance regulator affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pathogenic fungi. The appreciation of whether they are primarily responsible for or a consequence of an ineffective airway inflammation is important for future therapeutics development. OBJECTIVE: To characterize the impact of the tryptophan kynurenine pathway on pathogenic airway inflammation preventing effective fungal clearance in CF. METHODS: We studied the expression of the indoleamine 2,3-dioxygenase (IDO), the first enzyme in the kynurenine pathway of tryptophan degradation, in human and murine CF, the impact of IDO on lung inflammation and immunity in murine CF, and the potential role of tryptophan catabolism in pathogenesis and therapy of fungal-associated lung inflammation. MAIN RESULTS: IDO was defective in murine and human CF. Genetic and transcriptional regulatory mechanisms contributed to dysfunctional IDO activity that, in turn, correlated with imbalanced Th17/Treg cell responses to Aspergillus fumigatus in murine CF. Treatments enhancing IDO function or prevention of pathogenic Th17 cell activation, restored protective immunity to the fungus and improved lung inflammation in murine CF. CONCLUSIONS: This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO mimetic drugs may benefit CF patients.