HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria

Nature. 2012 Aug 9;488(7410):222-5. doi: 10.1038/nature11242.

Abstract

The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem−/− mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Bacterial Load
  • Cell Line
  • Citrobacter rodentium / immunology*
  • Citrobacter rodentium / pathogenicity*
  • Disease Models, Animal
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / microbiology
  • Enteropathogenic Escherichia coli
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Escherichia coli Infections
  • GPI-Linked Proteins / immunology
  • GPI-Linked Proteins / metabolism
  • Immunity, Mucosal / immunology*
  • Intestines / immunology
  • Intestines / microbiology
  • Ligands
  • Lung / immunology
  • Lung / microbiology
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mucous Membrane / immunology*
  • Mucous Membrane / metabolism
  • Mucous Membrane / microbiology*
  • Pneumococcal Infections / immunology
  • Pneumococcal Infections / microbiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Receptors, Tumor Necrosis Factor, Member 14 / deficiency
  • Receptors, Tumor Necrosis Factor, Member 14 / genetics
  • Receptors, Tumor Necrosis Factor, Member 14 / immunology
  • Receptors, Tumor Necrosis Factor, Member 14 / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • Streptococcus pneumoniae / immunology
  • Survival Rate

Substances

  • Antigens, CD
  • Cd160 protein, mouse
  • GPI-Linked Proteins
  • Ligands
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tnfrsf14 protein, mouse
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase