Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Aging / metabolism*
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Animals
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Cell Movement / drug effects
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Cellular Microenvironment / immunology
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Coronavirus Infections / immunology*
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Coronavirus Infections / metabolism
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Coronavirus Infections / virology
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Dendritic Cells / immunology
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Dendritic Cells / pathology*
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Disease Susceptibility
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Immunocompromised Host
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Influenza A virus / immunology
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Lung / immunology
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Lung / pathology
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Murine hepatitis virus / immunology
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Orthomyxoviridae Infections / immunology*
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Orthomyxoviridae Infections / metabolism
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Orthomyxoviridae Infections / virology
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Prostaglandin Antagonists / pharmacology
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Prostaglandin Antagonists / therapeutic use
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Prostaglandin D2 / biosynthesis
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Prostaglandin D2 / physiology*
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Receptors, CCR7 / biosynthesis
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Receptors, CCR7 / genetics
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Respiratory Syncytial Virus Infections / immunology*
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Respiratory Syncytial Virus Infections / metabolism
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Respiratory Syncytial Virus Infections / virology
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Respiratory Syncytial Viruses / immunology
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Severe Acute Respiratory Syndrome / immunology
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Severe Acute Respiratory Syndrome / metabolism
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Severe Acute Respiratory Syndrome / virology
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Severe acute respiratory syndrome-related coronavirus / immunology
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Specific Pathogen-Free Organisms
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T-Lymphocyte Subsets / immunology*
Substances
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Ccr7 protein, mouse
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Prostaglandin Antagonists
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Receptors, CCR7
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Prostaglandin D2