Viral acute lower respiratory infections rapidly impair CD8+ T lymphocyte functions through the PD-1/PD-L1 pathway (105.44)

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.