PD-1 deficiency exacerbateslung infection via metabolic rewiring and dysregulated neutrophil/T cell responses.

Abstract

BACKGROUND: Pulmonary(MAB) infection presents a therapeutic challenge, and while anti-programmed cell death protein 1(PD-1) therapy is clinically associated with increased MAB risk, yet the underlying immunomodulatory mechanisms remain elusive. METHODS: We established a PD-1-deficient mouse model of MAB infection and assessed bacterial clearance, immune responses, and metabolic alterations using colony counting, histopathology, flow cytometry, multiplex immunofluorescence, transcriptomics, and metabolic assays. RESULTS: PD-1mice showed increased susceptibility to MAB. Early infection was marked by elevated lung CD4T cells (Th17/Treg), diminished Th1 cells and neutrophils, and increased blood cytokines (IFN-γ, IL-21, IL-6, IL-27). Late infection featured further Th1 reduction, neutrophil accumulation, and NETs activation (H3cit, NE-DNA, MPO), along with reduced CXCL9 but elevated IL-6, IL-21, IL-27, CXCL10, and S100A8 in blood. Metabolic changes included decreased blood glucose, elevated lung ATP, and upregulation of HIF-1 pathway proteins (e.g., HK2, iNOS)., PD-1 deficiency suppressed glycolysis in T cells yet augmented it in neutrophils upon MAB infection. CONCLUSION: PD-1 deficiency disrupts T cell-neutrophil crosstalk via metabolic reprogramming, resulting in immune dysregulation and exacerbated infection. These findings underscore infection risks linked to PD-1/PD-L1 blockade, informing clinical safety and therapeutic strategies.