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 3

Elevated levels of PGD2 in uninfected and infected aged mice.

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Elevated levels of PGD2 in uninfected and infected aged mice. (A) An...
(A) An enzyme immunoassay was used to quantify PGD2 levels in the BALF, following the manufacturer’s instructions. n = 4 mice in each age per experiment. Data are representative of 3 independent experiments. *P < 0.05. (B) DP1 receptor expression on rDCs harvested from the lungs of naive mice or mice at 18 hours after infection with SARS-CoV or IAV was measured, as described in Methods. Data are representative of 3 independent experiments.