title: Age-related increases in PGD(2) 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 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.
authors: Department of Microbiology, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Jincun
authors: J
authors: Zhao
authors: Jingxian
authors: J
authors: Zhao
authors: Kevin
authors: K
authors: Legge
authors: Stanley
authors: S
authors: Perlman
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D060833:Cellular Microenvironment / Q000276:immunology; D018352:Coronavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D004198:Disease Susceptibility; D016867:Immunocompromised Host; D009980:Influenza A virus / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D011448:Prostaglandin Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D015230:Prostaglandin D2 / Q000096:biosynthesis / Q000502:physiology*; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: C515371:Ccr7 protein, mouse; D011448:Prostaglandin Antagonists; D054400:Receptors, CCR7; D015230:Prostaglandin D2