Commensal viruses maintain intestinal intraepithelial lymphocytes via noncanonical RIG-I signaling

Nat Immunol. 2019 Dec;20(12):1681-1691. doi: 10.1038/s41590-019-0513-z. Epub 2019 Oct 21.

Abstract

Much attention has focused on commensal bacteria in health and disease, but the role of commensal viruses is understudied. Although metagenomic analysis shows that the intestine of healthy humans and animals harbors various commensal viruses and the dysbiosis of these viruses can be associated with inflammatory diseases, there is still a lack of causal data and underlying mechanisms to understand the physiological role of commensal viruses in intestinal homeostasis. In the present study, we show that commensal viruses are essential for the homeostasis of intestinal intraepithelial lymphocytes (IELs). Mechanistically, the cytosolic viral RNA-sensing receptor RIG-I in antigen-presenting cells can recognize commensal viruses and maintain IELs via a type I interferon-independent, but MAVS-IRF1-IL-15 axis-dependent, manner. The recovery of IELs by interleukin-15 administration reverses the susceptibility of commensal virus-depleted mice to dextran sulfate sodium-induced colitis. Collectively, our results indicate that commensal viruses maintain the IELs and consequently sustain intestinal homeostasis via noncanonical RIG-I signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antigen-Presenting Cells / immunology*
  • Caliciviridae Infections / immunology*
  • Caliciviridae Infections / virology
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / virology
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism*
  • Dextran Sulfate
  • Disease Susceptibility
  • Homeostasis
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism
  • Interleukin-15 / metabolism
  • Intestines / immunology*
  • Intestines / virology
  • Intraepithelial Lymphocytes / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Norovirus / physiology*
  • Signal Transduction
  • Symbiosis / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Interferon Regulatory Factor-1
  • Interleukin-15
  • Irf1 protein, mouse
  • Dextran Sulfate
  • Ddx58 protein, mouse
  • DEAD Box Protein 58