Deletion of Dipeptidyl peptidase 3 in mice unleashes protective antibacterial immunity against Klebsiella pneumoniae

Klebsiella pneumoniae is a common cause of pneumonia, particularly in elderly and immunocompromised patients, often leading to sepsis. Over the past decades, the emergence of multi-drug resistant strains made the treatment of K. pneumoniae a big challenge. Recent studies have demonstrated that host defense plays a critical role in eradicating K. pneumoniae. The dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic metallopeptidase acting in the degradation of various bioactive peptides. In addition, it has been involved in the Nrf2 antioxidant pathway. Its high blood concentrations, related to massive cell death and inflammation, predict high risk organ dysfunction and mortality in patients with septic shock. To address the relevance of DPP3 in K. pneumoniae infections, we applied a model of lung infection in the DPP3 knock-out mice. We evaluated the mortality and the pulmonary and systemic bacterial load at different time points post infection. The levels of pro- and anti-inflammatory cytokines were measured, histopathological damage and inflammation were assessed in the lung. Results showed that DPP3 deficiency was associated with markedly decreased lung colonization and systemic bacterial burden, resulting in a significant survival advantage. Upon bacterial infection, DPP3-/- mice exhibited reduced tissue damage and weakened pulmonary and systemic inflammation compared with WT mice. Adoptive transfer experiment indicated that deficiency of DPP3 in immune cells was sufficient to enhance the lung bacterial clearance. Thus, we further used transcriptomics and cellular assays to define the specific role of DPP3 in lung immune cell biology. We found that lack of DPP3 induced transcriptional and metabolic programs characteristic of effector cells, associated with enhanced inflammatory signaling pathways. Accordingly, both innate and adaptive DPP3-deficient immune cells exerted more potent antimicrobial responses, particularly ROS and Th1/Th17 cytokines production. These findings point to DPP3 as novel immune checkpoint that shapes immunity by controlling the threshold for activation and resistance pathways. These