Year: 2012
Type: article
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.
DOI: 10.1172/jci62860
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: Vanderbilt University, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: Large-Scale Vaccinia Virus-Derived CTL Epitope Discovery, G1531600799, G153582612, G1764958080, G1951620746, G2043477120, G224138111, G2268269956, Molecular Immunology of Minor Histocompatibility Antigen, G2893040420, G3433274139, Medical Scientist Training Program, G4107354744, G4342999528, G4409390893, G4788269112, G560889077, G563474107, The Vanderbilt Institute for Clinical and Translational Research (VICTR) KL2, G5853943267, The Vanderbilt Institute for Clinical and Translational Research (VICTR) TL1, G640038255, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, G7243761488, G7520984233, G7653134492, Attenuated Strains of Human Metapneumovirus for Vaccines and Pathogenesis, G8489032239, G9000076948, G9000081609, G9000300101, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant, Host Determinants of Human Metapneumovirus Immunity and Pathogenesis
OpenAlex ID: W2047703405