Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection

Sci Rep. 2017 Jan 17:7:40720. doi: 10.1038/srep40720.

Abstract

Given the rapid spread of flaviviruses such as West Nile virus (WNV) and Zika virus, it is critical that we develop a complete understanding of the key mediators of an effective anti-viral response. We previously demonstrated that WNV infection of mice deficient in mitochondrial antiviral-signaling protein (MAVS), the signaling adaptor for RNA helicases such as RIG-I, resulted in increased death and dysregulated immunity, which correlated with a failure of Treg expansion following infection. Thus, we sought to determine if intrinsic MAVS signaling is required for participation of Tregs in anti-WNV immunity. Despite evidence of increased Treg cell division, Foxp3 expression was not stably maintained after WNV infection in MAVS-deficient mice. However, intrinsic MAVS signaling was dispensable for Treg proliferation and suppressive capacity. Further, we observed generation of an effective anti-WNV immune response when Tregs lacked MAVS, thereby demonstrating that Treg detection of the presence of WNV through the MAVS signaling pathway is not required for generation of effective immunity. Together, these data suggest that while MAVS signaling has a considerable impact on Treg identity, this effect is not mediated by intrinsic MAVS signaling but rather is likely an effect of the overproduction of pro-inflammatory cytokines generated in MAVS-deficient mice after WNV infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Flavivirus / physiology*
  • Flavivirus Infections / genetics
  • Flavivirus Infections / immunology*
  • Flavivirus Infections / metabolism*
  • Flavivirus Infections / virology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression
  • Immunophenotyping
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Signal Transduction*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • West Nile Fever
  • West Nile virus

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IPS-1 protein, mouse