Viral acute lower respiratory infections impair CD8+ T cells through PD-1
Autor: | Andrew K. Hastings, Melissa B. Downing, Kelli L. Boyd, Joyce E. Johnson, Sebastian Joyce, Sharon J. Tollefson, Pavlo Gilchuk, Monika Johnson, Annette S. Kim, John J. Erickson, John V. Williams |
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Rok vydání: | 2012 |
Předmět: |
Pyridines
viruses Programmed Cell Death 1 Receptor Mice Transgenic Respiratory Syncytial Virus Infections CD8-Positive T-Lymphocytes Biology medicine.disease_cause Virus HLA-B7 Antigen Mice Influenza A Virus H1N1 Subtype Antigen Human metapneumovirus Immunity Influenza Human Influenza A virus medicine Animals Humans Cytotoxic T cell Respiratory system Antigens Viral Lung Respiratory Tract Infections Paramyxoviridae Infections Imidazoles General Medicine biology.organism_classification Virology Up-Regulation Virus Diseases Respiratory Syncytial Virus Human Acute Disease Immunology Metapneumovirus Immunologic Memory CD8 Research Article Signal Transduction |
Zdroj: | Journal of Clinical Investigation |
ISSN: | 0021-9738 |
Popis: | 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. |
Databáze: | OpenAIRE |
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