Abstract Viruses are leading causes of severe acute lower respiratory infection (LRI) yet evoke incomplete immunity as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid CD8+ cytotoxic T lymphocyte (CTL) functional impairment in the respiratory tract via programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated pulmonary CTL impairment occurred as early as day 7 during human metapneumovirus or influenza virus infections. Viral antigen alone was sufficient to drive PD-1 upregulation, but PD-1 ligation by infection-induced PD-L1 was required for impairment. Therapeutic inhibition of PD-1 signaling prevented CTL impairment and reduced viral titers without exacerbating lower airway pathology. Additionally, PD-1 and PD-L1 were upregulated in the lungs of pediatric patients with severe H1N1 pandemic influenza virus or respiratory syncytial virus infections. Our results indicate that PD-1 signaling mediates CTL functional impairment rapidly at primary sites of infection due to the presence of local viral antigen and represents a conserved response against different viruses that cause serious LRI in children and adults. Therefore, the PD-1/PD-L1 pathway may represent a novel target for therapeutics and vaccine development against respiratory viruses.

Viruses are leading causes of severe acute lower respiratory infections (LRIs). These infections evoke incomplete immunity, as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid pulmonary CD8+ cytotoxic T lymphocyte (TCD8) functional impairment via programmed death-1/programmed death ligand-1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated TCD8 impairment occurred acutely in mice following infection with human metapneumovirus or influenza virus. Viral antigen was sufficient for PD-1 upregulation, but induction of PD-L1 was required for impairment. During secondary viral infection or epitope-only challenge, memory TCD8 rapidly reexpressed PD-1 and exhibited severe functional impairment. Inhibition of PD-1 signaling using monoclonal antibody blockade prevented TCD8 impairment, reduced viral titers during primary infection, and enhanced protection of immunized mice against challenge infection. Additionally, PD-1 and PD-L1 were upregulated in the lungs of patients with 2009 H1N1 influenza virus, respiratory syncytial virus, or parainfluenza virus infection. These results indicate that PD-1 mediates TCD8 functional impairment during acute viral infection and may contribute to recurrent viral LRIs. Therefore, the PD-1/PD-L1 pathway may represent a therapeutic target in the treatment of respiratory viruses.