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Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice
Open accessAbstract
The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell-extrinsic functions. Here, we show that increases in prostaglandin D(2) (PGD(2)) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration associated with virus-specific defects in T cell responses and was not a result of cell-intrinsic defect, rather it reflected the observed age-dependent increases in PGD(2) expression. Blocking PGD(2) function with small-molecule antagonists enhanced rDC migration, T cell responses, and survival. This effect correlated with upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. Our results suggest that inhibiting PGD(2) function may be a useful approach to enhance T cell responses against respiratory viruses in older humans.
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“Age-related elevations of eicosanoid levels, especially prostaglandin D2 (PGD2), were detected in mouse models of SARS-CoV infection133.”
From COVID-19 and cellular senescence (2023) · cites this paper as [133]
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“During SARS-CoV-1 infection, lung DCs from older mice displayed an impaired ability to migrate to the draining lymph node, which negatively affected subsequent T cell priming125.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [125]
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“…immune evasion by SARS-CoV-2 may limit T cell priming (Blanco-Melo et al., 2020; Vabret et al., 2020), and there is the possibility of fewer professional antigen presenting cells in the lungs with advanced age, as has been seen in small animal models of SARS (Chen et al., 2010; Zhao et al., 2011).”
Metadata
- Authors
- Zhao, J., Zhao, J., Legge, K., & Perlman, S.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Perlman, Stanley
- Venue
- Journal of Clinical Investigation
- Published
- 2011-12-01
- Volume
- 121
- Issue
- 12
- Pages
- 4921-4930
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3226008
- OpenAlex
- W2115101593
- Cited by
- 265
- References
- 60
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 8 · 2023: 15 · 2022: 26 · 2021: 42 · 2020: 66 · 2019: 5 · 2018: 10 · 2017: 12 · 2016: 14 · 2015: 9 · 2014: 15 · 2013: 16 · 2012: 6
- FWCI
- 5.68
- 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
- National Institutes of Health (PO1AI060699, AI060699, AI071085)
- National Institute of Allergy and Infectious Diseases (R01AI071085, R56 AI79424, R01AI091322, R56AI079424, P01AI060699)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
- Keywords
- prostaglandin D2, dendritic cell migration, aging, respiratory viral infections, T cell response, draining lymph nodes, CCR7, chemokine receptors, age-related immunosenescence, lung immunity
- MeSH terms
- Aging, Animals, Cell Movement, Dendritic Cells, Disease Susceptibility, Murine hepatitis virus, Lung, Lymph Nodes, Lymphocyte Activation, Mice, Inbred C57BL, Orthomyxoviridae Infections, Influenza A virus, Prostaglandin Antagonists, Respiratory Syncytial Viruses, Specific Pathogen-Free Organisms, Prostaglandin D2, T-Lymphocyte Subsets, Immunocompromised Host, Coronavirus Infections, Respiratory Syncytial Virus Infections, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome-related coronavirus, Mice, Receptors, CCR7, Cellular Microenvironment
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