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

Erickson, John J.; Gilchuk, Pavlo; Hastings, Andrew K.; Tollefson, Sharon J.; Johnson, Monika; Downing, Melissa B.; Boyd, Kelli L.; Johnson, Joyce E.; Kim, Annette S.; Joyce, Sebastian; Williams, John V.

doi:10.1172/jci62860

Cited by 203T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersRespiratory viral infections research

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

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Erickson, John J., Gilchuk, Pavlo, Hastings, Andrew K., Tollefson, Sharon J., Johnson, Monika, Downing, Melissa B., Boyd, Kelli L., Johnson, Joyce E. +3 more·2012·Journal of Clinical Investigation

DOI 10.1172/jci62860PMC PMC3408742

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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.

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Expression of inhibitory markers is not always a sign of immune exhaustion, because receptors may be expressed individually during conventional immune responses.
“It should be noted that expression of inhibitory markers is not always a sign of immune exhaustion, because the receptors may be expressed individually during conventional immune responses (18).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [18]

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Authors: Erickson, J. J., Gilchuk, P., Hastings, A. K., Tollefson, S. J., Johnson, M., Downing, M. B., Boyd, K. L., Johnson, J. E., Kim, A. S., Joyce, S., & Williams, J. V.
Affiliations: Vanderbilt University (US)
Corresponding author: Williams, John V.
ORCID: Erickson, John J.
Gilchuk, Pavlo
Hastings, Andrew K.
Boyd, Kelli L.
Johnson, Joyce E.
Kim, Annette S.
Joyce, Sebastian
Williams, John V.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2012-08-01
Volume: 122
Issue: 8
Pages: 2967-2982
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci62860
PMC: PMC3408742
OpenAlex: W2047703405
Cited by: 203
References: 83
Citations by year: 2026: 11 · 2025: 16 · 2024: 10 · 2023: 18 · 2022: 9 · 2021: 19 · 2020: 20 · 2019: 16 · 2018: 21 · 2017: 4 · 2016: 14 · 2015: 13 · 2014: 17 · 2013: 15
FWCI: 6.29
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Vanderbilt University (P30 CA68485, UL1 RR024975-01, UL1 RR024975, CA68485)
Georgia Clinical and Translational Science Alliance (UL1 RR024975, UL1 RR024975-01, RR024975)
National Institutes of Health (n01ai40079-5-0-1, AI042286, AI040079, DK 058404, CA68485, RR024975)
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center (DK-058404, P30 CA68485)
National Heart, Lung, and Blood Institute (R01HL054977, HL054977)
National Cancer Institute (P30 CA 68485, P30CA068485)
National Institute of General Medical Sciences (T32GM007347, GM-007347)
National Institute of Allergy and Infectious Diseases (AI042286, AI085062, AI-082417, R21AI082417, N01 AI040079, R01AI085062)
National Institute of Diabetes and Digestive and Kidney Diseases (DK058404, P30DK058404)
National Center for Research Resources (RR024975, KL2RR024977, TL1RR024978, UL1RR024975, RR024975‐01)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
Keywords: acute lower respiratory tract infection, respiratory viral infections, CD8+ T cells, cytotoxic T lymphocytes, PD-1, PD-L1, PD-1/PD-L1 signaling, human metapneumovirus, influenza virus, respiratory syncytial virus, parainfluenza virus, 2009 H1N1 influenza, memory T cells, recurrent viral infections, T cell exhaustion, monoclonal antibody blockade, immunotherapy
MeSH terms: Acute Disease, Animals, Antigens, Viral, Humans, Imidazoles, Immunologic Memory, Influenza, Human, Lung, Mice, Transgenic, Pyridines, Respiratory Tract Infections, Virus Diseases, Signal Transduction, HLA-B7 Antigen, Up-Regulation, Respiratory Syncytial Virus, Human, Paramyxoviridae Infections, Respiratory Syncytial Virus Infections, CD8-Positive T-Lymphocytes, Metapneumovirus, Mice, Influenza A Virus, H1N1 Subtype, Programmed Cell Death 1 Receptor

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

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