Viral acute lower respiratory infections impair CD8+ T cells through PD-1
John J. Erickson, … , Sebastian Joyce, John V. Williams
John J. Erickson, … , Sebastian Joyce, John V. Williams
Published July 17, 2012
Citation Information: J Clin Invest. 2012;122(8):2967-2982. https://doi.org/10.1172/JCI62860.
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Research Article Immunology

Viral acute lower respiratory infections impair CD8+ T cells through PD-1

Abstract

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.

Authors

John J. Erickson, Pavlo Gilchuk, Andrew K. Hastings, Sharon J. Tollefson, Monika Johnson, Melissa B. Downing, Kelli L. Boyd, Joyce E. Johnson, Annette S. Kim, Sebastian Joyce, John V. Williams

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Figure 3

Viral infection is required for pulmonary TCD8 impairment and PD-1 upregulation.

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Viral infection is required for pulmonary TCD8 impairment and PD-1 upreg...
(A and B) B6 mice were infected with IAV (strain A/34/PR/8), and the lung TCD8 response (A) and PD-1 expression (B) were assessed at days 7 and 14 after infection for the H2-Db/NP366 epitope. (C and D) B7tg mice were immunized i.n. with M195 peptide-loaded, LPS-matured DCs, and the lung M195-specific TCD8 response (C) and PD-1 expression (D) were quantified. (E and F) B7tg mice were infected with HMPV and then challenged at least 50 days later with either virus (HMPV) or M195-DCs delivered i.n. Lung lymphocytes were harvested at day 7 after challenge, and the TCD8 response (E) and PD-1 expression (F) were quantified. PD-1 expression on total lung CD8+ lymphocytes and epitope-specific CD8+ T cells are shown (B, D, and F). Each symbol represents an individual mouse, while horizontal lines denote the mean for each group. Data are combined from 2 independent experiments with 5 individual mice per time point per experiment. ###P < 0.0005 (2-tailed paired t test).