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

J Clin Invest. 2011 Dec;121(12):4921-30. doi: 10.1172/JCI59777. Epub 2011 Nov 21.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / metabolism*
  • Animals
  • Cell Movement / drug effects
  • Cellular Microenvironment / immunology
  • Coronavirus Infections / immunology*
  • Coronavirus Infections / metabolism
  • Coronavirus Infections / virology
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology*
  • Disease Susceptibility
  • Immunocompromised Host
  • Influenza A virus / immunology
  • Lung / immunology
  • Lung / pathology
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Murine hepatitis virus / immunology
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Prostaglandin Antagonists / pharmacology
  • Prostaglandin Antagonists / therapeutic use
  • Prostaglandin D2 / biosynthesis
  • Prostaglandin D2 / physiology*
  • Receptors, CCR7 / biosynthesis
  • Receptors, CCR7 / genetics
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / metabolism
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Viruses / immunology
  • SARS Virus / immunology
  • Severe Acute Respiratory Syndrome / immunology
  • Severe Acute Respiratory Syndrome / metabolism
  • Severe Acute Respiratory Syndrome / virology
  • Specific Pathogen-Free Organisms
  • T-Lymphocyte Subsets / immunology*

Substances

  • Ccr7 protein, mouse
  • Prostaglandin Antagonists
  • Receptors, CCR7
  • Prostaglandin D2