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Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice.

Identifieur interne : 002155 ( Main/Exploration ); précédent : 002154; suivant : 002156

Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice.

Auteurs : Jincun Zhao [États-Unis] ; Jingxian Zhao ; Kevin Legge ; Stanley Perlman

Source :

RBID : pubmed:22105170

Descripteurs français

English descriptors

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.

DOI: 10.1172/JCI59777
PubMed: 22105170


Affiliations:


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<term>Cellular Microenvironment (immunology)</term>
<term>Coronavirus Infections (immunology)</term>
<term>Coronavirus Infections (metabolism)</term>
<term>Coronavirus Infections (virology)</term>
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<term>Cellules dendritiques (anatomopathologie)</term>
<term>Cellules dendritiques (immunologie)</term>
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<front>
<div type="abstract" xml:lang="en">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.</div>
</front>
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