Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice
Jincun Zhao, Jingxian Zhao, Kevin Legge, Stanley Perlman
Jincun Zhao, Jingxian Zhao, Kevin Legge, Stanley Perlman
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Research Article

Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice

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 D2 (PGD2) 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 PGD2 expression. Blocking PGD2 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 PGD2 function may be a useful approach to enhance T cell responses against respiratory viruses in older humans.

Authors

Jincun Zhao, Jingxian Zhao, Kevin Legge, Stanley Perlman

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Figure 5

Treatment with PGD2 antagonist BW A868C enhances rDC migration and T cell responses in SARS-CoV–infected mice.

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Treatment with PGD2 antagonist BW A868C enhances rDC migration and T cel...
(A) Twelve-month-old mice were inoculated i.n. with 50 μl 8 mM CFSE. Six hours after instillation, mice were infected with SARS-CoV together with BW A868C or vehicle. After 18 hours, single-cell suspensions were prepared from lung DLNs (numbers represent the percentage of CFSE+ cells within the CD11c+MHCII+ DC population). Total CFSE+ DC numbers per LN are also shown. n = 4 mice for each age per experiment. Data are representative of 5 independent experiments. *P < 0.05. (B) Lung cells were harvested from 12-month-old B6 mice 6 days after SARS-CoV infection. Kb/S436 tetramer staining and total numbers of CD8 T cells and of Kb/S436 tetramer+ CD8 T cells are shown. Numbers represent the percentages of tetramer+ CD8 T cells. n = 4–6 mice/group/experiment. Data are representative of 7 independent experiments. *P < 0.05. (C) In vivo cytotoxicity assays were performed on day 6 p.i., and the percentage of killing was calculated, as described in Methods (numbers represent the percentage of cells labeled with different concentrations of CFSE). n = 4–6 mice/group/experiment. Data are representative of 2 independent experiments. *P < 0.05. Twelve-month-old mice were i.n. infected with 1 × 104 PFUs SARS-CoV virus with or without BW A868C. (D) Viral titers are expressed as PFU/g tissue. n = 4 mice/group/time point. Data are representative of 2 independent experiments. *P < 0.05. (E) Mortality was monitored daily. n = 12 mice in vehicle group; n =12 mice in BW A868C group. P = 0.0007, determined by a Kaplan-Meier survival test.