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 4

Cognate viral antigen in the presence of active LRI is required for PD-1 induction and TCD8 impairment.

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Cognate viral antigen in the presence of active LRI is required for PD-1...
(A) Experimental strategy for B and C: B7tg mice were immunized i.n. with VACV A34R-loaded or HMPV M195-loaded DCs, and lung lymphocytes were harvested at either day 14 after immunization (A34R immunization) or day 7 after HMPV challenge (both A34R and M195 immunizations). (B) The A34R- and M195-specific TCD8 responses were quantified in each group of mice as indicated. (C) PD-1 expression is shown as either representative histograms, percentage positive, or MFI. (D and E) Mice were immunized i.n. with M195-loaded DCs, and then 50 μg of either an irrelevant peptide (Mock) or M195 peptide (M195) was administered daily i.n. for 7 days. The M195-specific TCD8 response (D) and PD-1 expression (E) following repeated peptide administration were quantified. Data in B are combined from 3 independent experiments, while data in C–E are representative of at least 2 independent experiments with 4–6 individual mice per group per experiment. #P < 0.05, ###P < 0.0005 (2-tailed paired t test). *P < 0.05, **P < 0.005, ***P < 0.0005 (1-way ANOVA with Bonferroni post-test [C] or 2-tailed Student’s t test [E]).