Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection

J Virol. 2010 Dec;84(24):12895-902. doi: 10.1128/JVI.01273-10. Epub 2010 Oct 6.

Abstract

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not been examined. In this study, primary isolated DCs from cord blood and adult peripheral blood were compared after RSV infection. Transcriptional profiling and biological network analysis identified transforming growth factor beta (TGF-β) and associated signaling molecules as differentially regulated in the two age groups. TGF-β1 was decreased in RSV-infected adult-blood DCs but increased in RSV-infected cord blood DCs. Coculture of adult RSV-infected DCs with autologous T cells induced secretion of gamma interferon (IFN-γ), interleukin 12p70 (IL-12p70), IL-2, and tumor necrosis factor alpha (TNF-α). Conversely, coculture of cord RSV-infected DCs and autologous T cells induced secretion of IL-4, IL-6, IL-1β, and IL-17. Addition of purified TGF-β1 to adult DC-T-cell cocultures reduced secretion of IFN-γ, IL-12p70, IL-2, and TNF-α, while addition of a TGF-β chemical inhibitor to cord DC-T-cell cocultures increased secretion of IL-12p70. These data suggest that TGF-β acts as a major regulator of RSV DC-T-cell responses, which could contribute to immunopathology during infancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cell Differentiation
  • Child
  • Dendritic Cells / virology
  • Fetal Blood / metabolism
  • Fetal Blood / virology
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Laryngeal Neoplasms / metabolism
  • Laryngeal Neoplasms / pathology
  • Laryngeal Neoplasms / virology
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Viruses / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • Transforming Growth Factor beta / physiology*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Biomarkers, Tumor
  • Interleukin-2
  • Interleukin-6
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Interferon-gamma