Dipeptidyl peptidase 3 sets the threshold for immune activation and survival during experimental bacterial infection

Effective host defense requires coordinated regulation of immune activation, metabolism, and redox balance, yet how these processes are integrated remains unclear. Here, we identify dipeptidyl peptidase 3 (Dpp3) as a regulator of immune activation thresholds during bacterial infection. Dpp3−/− mice display enhanced resistance to Klebsiella pneumoniae, with early divergence in bacterial burden, improved survival, preserved tissue architecture, and reduced systemic inflammation. Adoptive transfer experiments demonstrate that Dpp3-deficient immune cells are sufficient to confer protection, indicating a cell-intrinsic effect. Mechanistically, Dpp3 deficiency impairs inducible Nrf2 stabilization, resulting in amplified ROS accumulation and enhanced NF-κB–associated responses. Integrated metabolomic, bioenergetic, and proteomic analyses reveal coordinated mitochondrial remodeling and activation of inflammatory signaling networks, consistent with a metabolically primed immune state. Collectively, these findings establish Dpp3 as a systems-level regulator integrating redox control and immunometabolism to calibrate antimicrobial responses during infection. Various immune cells and mediators have been shown to be important in the defence against Klebsiella pneumoniae. Here the authors investigate the function of dipeptidyl peptidase 3 (Dpp3) and show that Dpp3−/− immune cells can improve protection to Klebsiella in mice and that this involves mitochondrial functional changes and increased inflammatory responses.