Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection

Nat Immunol. 2015 Jul;16(7):698-707. doi: 10.1038/ni.3180. Epub 2015 May 25.

Abstract

The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cytokines / genetics
  • Cytokines / immunology*
  • Cytokines / pharmacology
  • Dogs
  • Drug Synergism
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology
  • Gene Expression / drug effects
  • Gene Expression / immunology*
  • HT29 Cells
  • Humans
  • Immunoblotting
  • Interleukins / genetics
  • Interleukins / immunology*
  • Interleukins / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestines / immunology
  • Intestines / virology
  • Madin Darby Canine Kidney Cells
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rotavirus Infections / genetics
  • Rotavirus Infections / immunology*
  • Rotavirus Infections / virology
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism
  • Vero Cells

Substances

  • Cytokines
  • Interleukins
  • Receptors, Cytokine
  • STAT1 Transcription Factor
  • interferon-lambda protein, mouse
  • interleukin-22