| Viral acute lower respiratory infections impair CD8+ T cells through PD-1. | |
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MedLine Citation:
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PMID: 22797302 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-07-17 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-08-01 Completed Date: 2012-10-25 Revised Date: 2013-01-11 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 2967-82 Citation Subset: AIM; IM |
Affiliation:
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Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute Disease Animals Antigens, Viral CD8-Positive T-Lymphocytes / immunology* HLA-B7 Antigen / genetics Humans Imidazoles Immunologic Memory Influenza A Virus, H1N1 Subtype Influenza, Human / immunology, metabolism Lung / immunology, metabolism Metapneumovirus Mice Mice, Transgenic Paramyxoviridae Infections / immunology, metabolism Programmed Cell Death 1 Receptor / antagonists & inhibitors, metabolism* Pyridines Respiratory Syncytial Virus Infections / immunology, metabolism Respiratory Syncytial Virus, Human Respiratory Tract Infections / immunology*, metabolism* Signal Transduction Up-Regulation Virus Diseases / immunology*, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AI040079/AI/NIAID NIH HHS; AI042286/AI/NIAID NIH HHS; AI082417/AI/NIAID NIH HHS; AI085062/AI/NIAID NIH HHS; DK058404/DK/NIDDK NIH HHS; GM007347/GM/NIGMS NIH HHS; HL054977/HL/NHLBI NIH HHS; KL2 RR024977/RR/NCRR NIH HHS; KL2 TR000446/TR/NCATS NIH HHS; P30 CA68485/CA/NCI NIH HHS; TL1 RR024978/RR/NCRR NIH HHS; TL1 TR000447/TR/NCATS NIH HHS; UL1 RR024975/RR/NCRR NIH HHS; UL1 RR024975-01/RR/NCRR NIH HHS; UL1 TR000445/TR/NCATS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/57G709; 0/Antigens, Viral; 0/HLA-B*07:02 antigen; 0/HLA-B7 Antigen; 0/Imidazoles; 0/PDCD1 protein, human; 0/Pdcd1 protein, mouse; 0/Programmed Cell Death 1 Receptor; 0/Pyridines |
| Comments/Corrections | |
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