Collaboration Between Macrophages and Vaccine-Induced CD4⁺ T Cells Confers Protection Against Lethal Pseudomonas aeruginosa Pneumonia During Neutropenia

The usefulness of vaccine-based strategies to prevent lethal bacterial infection in a host with neutropenia is not well-defined. Here, we show in a neutropenic mouse model that immunity induced by mucosal vaccination with a live-attenuated Pseudomonas aeruginosa vaccine is protective against lethal P. aeruginosa pneumonia caused by both vaccine-homologous and vaccine-heterologous strains, whereas passive immunization confers only vaccine-homologous protection. Cells in the macrophage lineage served as crucial innate cellular effectors in the neutropenic host after active immunization. Vaccine efficacy was CD4⁺ T-cell dependent and associated with accumulation of macrophage-lineage cells in the alveolar space after infection, as well as with enhanced P. aeruginosa clearance from the lung. Adaptive CD4⁺ T cells produced granulocyte-macrophage colony-stimulating factor (GM-CSF) on restimulation in vitro, and local GM-CSF was critical for vaccine efficacy. Thus, collaboration between the innate and adaptive effectors induced by mucosal vaccination can overcome neutropenia and confer protection against lethal bacterial infection in the profoundly neutropenic host.