Document Detail


Viral acute lower respiratory infections impair CD8+ T cells through PD-1.
MedLine Citation:
PMID:  22797302     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-17
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-01     Completed Date:  2012-10-25     Revised Date:  2014-04-22    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2967-82     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
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:
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; R01 AI085062/AI/NIAID 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:
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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