Viral acute lower respiratory infections impair CD8+ T cells through PD-1
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
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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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 2

Pulmonary TCD8 are impaired and upregulate PD-1 during HMPV LRI.

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Pulmonary TCD8 are impaired and upregulate PD-1 during HMPV LRI. Splee...
Spleen (A and B) and lung (C and D) lymphocytes were isolated from B7tg mice at the indicated times after HMPV infection. Representative histograms from day 7 after infection (A and C) and combined data from several time points (B and D) enumerate the TCD8 response directed against the M195 epitope. Numbers in flow plots indicate the percentage of CD8+ T cells that either bind to M195 tetramer or respond to restimulation with M195 peptide by mobilizing CD107a to the cell surface (i.e., degranulating) or producing IFN-γ. (E) M195-specific TCD8 response at day 42 after primary infection (Before) and then at day 7 after challenge. (F) N198-specific TCD8 response at day 14 after infection. (G) Representative flow cytometry plots demonstrating PD-1 expression versus M195 tetramer staining at day 14 after infection in the lung. Numbers in each quadrant indicate the percentage of CD8+ T cells. (H) Kinetics of PD-1 expression on spleen or lung M195-specific CD8+ T cells. Arrow indicates the time at which mice were challenged with HMPV (day 42 after primary infection). Data are representative of at least 2 independent experiments with 4–5 individual mice per time point. Twenty-thousand CD8+ T cells were counted for the spleen and 10,000 for the lung. #P < 0.05, ‡P < 0.005, ###P < 0.0005 (2-tailed paired t test); values in D–F are relative to tetramer+ cells analyzed in parallel from the same mice at the same time point.