Pseudomonas aeruginosa induces the generation of pathogenic IFNγ+Th17 cells that promote lung damage and chronic inflammation in cystic fibrosis
Abstract 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.
Authors
- Francesco Blasi (ORCID: https://orcid.org/0000-0002-2285-9970)
- Gianmarco Conte (ORCID: https://orcid.org/0009-0007-5484-091X)
- A. Palleschi (ORCID: https://orcid.org/0000-0003-4510-5167)
- Javier Cibella (ORCID: https://orcid.org/0000-0002-2895-8152)
- Daniela Guidone (ORCID: https://orcid.org/0000-0002-9301-8095)
- Helle Krogh Johansen (ORCID: https://orcid.org/0000-0003-0268-3717)
- Diletta Dolfini (ORCID: https://orcid.org/0000-0002-5346-6096)
- Mirko Ronzio (ORCID: https://orcid.org/0000-0002-4699-4405)
- Miriam Ascagni (ORCID: https://orcid.org/0000-0001-5458-269X)
- Enrico Lugli (ORCID: https://orcid.org/0000-0002-1964-7678)
- Paolo Landini (ORCID: https://orcid.org/0000-0003-0999-426X)
- Moira Paroni (ORCID: https://orcid.org/0000-0001-8199-3128)
- Clelia Peano (ORCID: https://orcid.org/0000-0001-7055-3629)
- Simone Puccio (ORCID: https://orcid.org/0000-0003-4007-4365)
- Matteo Chiara (ORCID: https://orcid.org/0000-0003-3983-4961)
- Elio Rossi (ORCID: https://orcid.org/0000-0002-2042-608X)
- Irene Dusetti (ORCID: https://orcid.org/0009-0000-9220-1819)
- Riccardo Orlandi (ORCID: https://orcid.org/0000-0002-4113-1598)
- Luis J. Galietta
- Francesco Damarco
- Eugenia Ricciardelli
- Søren Molin
- Andrea Gramegna
Institutions
- University of Copenhagen (DK)
- University of Milan (IT)
- Novo Nordisk Foundation (DK)
- Rigshospitalet (DK)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Human Technopole (IT)
- Telethon Institute Of Genetics And Medicine (IT)
- National Research Council (IT)
- IRCCS Humanitas Research Hospital (IT)
- University of Naples Federico II (IT)
- Technical University of Denmark (DK)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1038/s41564-026-02469-2
- Primary Topic
- Cystic Fibrosis Research Advances
- Type
- article
- Field-Weighted Citation Impact
- 0.00