Pseudomonas aeruginosa induces the generation of pathogenic IFNγ+Th17 cells that promote lung damage and chronic inflammation in cystic fibrosis.

Cystic fibrosis (CF) involves cycles of bacterial infection and sustained inflammation. IFNγ+Th17 cells are implicated in chronic inflammation, yet their role in CF remains undefined. Here we identify two pathogenic Th17 subsets, Th1/17+ and pro-inflammatory Th17 (pTh17) cells, selectively enriched in CF lungs colonized by Pseudomonas aeruginosa. These pathogenic subsets derive from protective conventional Th17 (cTh17) precursors and, following activation, directly disrupt pulmonary epithelial integrity and trigger exaggerated inflammatory responses. Transcriptomic and T cell receptor profiling reveal in situ reprogramming and clonal selection of Th1/17+ and pTh17 cells in CF lungs. Mechanistically, clinical P. aeruginosa strains persist within dendritic cells and induce a polarizing IL-1β/IL-23 cytokine axis that promotes IFNγ+Th17 differentiation over classical Th1 lineage commitment. P. aeruginosa early isolates, lacking chronic adaptation signatures, still potently reprogramme cTh17 cells, inducing a transcriptional programme that mirrors CF lung-resident Th1/17+ and pTh17 profiles. These findings show that P. aeruginosa subverts mucosal immunity and establishes a self-sustaining immunopathological loop, offering potential targets for CF precision therapies.