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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
Jincun Zhao, … , Kevin Legge, Stanley Perlman
Jincun Zhao, … , Kevin Legge, Stanley Perlman
Published November 21, 2011
Citation Information: J Clin Invest. 2011;121(12):4921-4930. https://doi.org/10.1172/JCI59777.
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Research Article Article has an altmetric score of 33

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

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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 2

Age-dependent decreases in virus-specific CD8 T cell responses in lungs of SARS-CoV– and IAV-infected mice.

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Age-dependent decreases in virus-specific CD8 T cell responses in lungs ...
Lung cells were harvested from young and aged B6 mice 6 days or 8 days after SARS-CoV or IAV infection, respectively. (A) Tetramer staining for epitopes S436 (Tet-S436) and PA224 (Tet-PA224) (numbers represent the percentage of tetramer+ CD8 T cells), (B) total numbers of CD8 T cells, and (C) frequency and (D) numbers of tetramer+ or IFN-γ+ virus-specific CD8 T cells for epitopes S436 and PA224 are shown. *P < 0.05. (E) Geometric mean of fluorescence intensity (MFI) of IFN-γ production upon peptide stimulation is shown (young, 6 weeks old; old, 12 months old, SARS-CoV infected and 22 months old, IAV infected). n = 4–6 mice/group/experiment; *P < 0.05. Data are representative of 4–5 independent experiments. Mice of various ages were i.n. infected with (F) SARS-CoV or (G) IAV virus. Mortality was monitored daily. P values were determined by Kaplan-Meier survival tests (for SARS-CoV–infected mice, 6-week-old mice, n = 14; 6-month-old mice, n = 8; 12-month-old mice, n = 10; 22-month-old mice, n = 8; for 6-week-old versus 12-month-old or 22-month-old, P < 0.005) (for IAV-infected mice, 6-week-old mice, n = 10; 6-month-old mice, n = 8; 12-month-old mice, n = 8; 22-month-old mice, n = 10; for 6-week-old versus 22-month-old mice, P = 0.04).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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