During lung infection Psudomonas aeruginosa (Pa) undergoes a characteristic evolutionary adaptation that leads to a greater ability to persist within CF airways, triggering a continuous and dysregulated activation of the immune system. These important Pa adaptation mechanisms suggest that in the late stages of the disease an overly activation of the immune system, rather than the Pa virulence, is the main cause of lung function decline in CF. In this respect, the recent identification of a new subset of T lymphocytes (Th1/17) has represented a crucial turning point. These cells produce pro-inflammatory molecules (cytokines IFN-γ and IL-17) that have been found highly enriched in CF patients and that strongly correlated with disease severity and lung injury, thus suggesting  a potential pathogenic role for these Th1/17 cells in CF. In this project, we investigated the role of Th1/17 cells in CF and the immunological mechanisms that lead to their activation during chronic Pa lung infections. Our results demonstrated a selective enrichment of specific Th1/17 subsets in the lungs of CF patients with Pa chronic infection compared to non-CF patients. Moreover, the analysis of interaction between immune cells and clinical Pa strains, isolated from CF lungs at different time points during chronic infection, revealed a significant higher ability of Pa strains isolated during late stage of the disease to trigger the activation of pathogenic Th1/17 cells. Finally, using a combination of functional-immunological approaches and  cutting-edge technologies (RNA sequencing) we identified both genes exclusively expressed in lung-infiltrating Th1/17 cells activated by Pa, and also Pa genes selectively expressed in clinical strains that induce release of pro-inflammatory cytokines involved in pathogenic Th1/17 activation in the CF lungs. Thanks to this project we identified new potential therapeutic targets that, after further characterization and functional validation, will pave the way for totally new pharmaceutical strategies able to counteract the pathogenic inflammation, possibly also by targeting Pa virulence determinants, thus providing a new precision medicine approach that might have an unprecedented impact on future CF treatments.