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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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 1

rDC migration to DLNs progressively decreases in aged mice.

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rDC migration to DLNs progressively decreases in aged mice. (A) Six-week...
(A) Six-week-old, six-month-old, twelve-month-old, and twenty-two–month-old mice were i.n. inoculated with 50 μl 8 mM CFSE. Six hours after instillation, mice were infected with SARS-CoV, IAV, RSV, or MHV-1. Naive mice inoculated with 200 μg/75 μl OVA-FITC served as controls. After 18 hours, single-cell suspensions were prepared from lung DLNs. The numbers represent the percentage of CFSE+ cells within the CD11c+MHCII+ DC population per LN. (B) Total CFSE+ DC numbers per LN, (C) the time course of rDC migration to the DLNs, (D) fold increase in DLN cellularity relative to that of naive mice, and (E) the proportion of CD11b+ and CD103+ populations among CFSE+CD11c+MHCII+ rDCs in DLNs are also shown. (F) CD86 expression on rDCs in the lung 18 hours p.i. n = 4 mice in each group for each experiment. Data are representative of 5–10 independent experiments. *P <0.05 versus 6 week.