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

Erickson JJ, Gilchuk P, Hastings AK, Tollefson SJ, Johnson M, Downing MB, Boyd KL, Johnson JE, Kim AS, Joyce S, Williams JV
J Clin Invest. 2012 122 (8): 2967-82

PMID: 22797302 · PMCID: PMC3408742 · DOI:10.1172/JCI62860

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.

MeSH Terms (23)

Acute Disease Animals Antigens, Viral CD8-Positive T-Lymphocytes HLA-B7 Antigen Humans Imidazoles Immunologic Memory Influenza, Human Influenza A Virus, H1N1 Subtype Lung Metapneumovirus Mice Mice, Transgenic Paramyxoviridae Infections Programmed Cell Death 1 Receptor Pyridines Respiratory Syncytial Virus, Human Respiratory Syncytial Virus Infections Respiratory Tract Infections Signal Transduction Up-Regulation Virus Diseases

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