Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9

PLoS One. 2018 Jul 11;13(7):e0200546. doi: 10.1371/journal.pone.0200546. eCollection 2018.

Abstract

Infection with the Epstein-Barr virus (EBV) has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have previously reported that DNA from this virus enhances production of the pro-autoimmune interleukin 17A (IL-17A) in mice. In this study we assessed the effect of EBV DNA on regulatory T cell programming and examined whether it mediated its effects via Toll-like receptor 9 (TLR9) in mice; moreover, we evaluated whether EBV DNA in humans had similar effects to those seen in mice. For this purpose, we assessed the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects and matched controls. A modulatory effect for the viral DNA was observed for regulatory T cell markers with an inhibitory effect observed for CTLA4 expression in the EBV DNA-treated mice. To examine whether TLR9 mediated the detection of EBV DNA and enhancement of IL-17A production, mouse peripheral blood mononuclear cells were treated with the DNA in the presence or absence of the TLR9 inhibitor ODN 2088. Subsequently, IL-17A production from these cells was assessed. Treatment with the TLR9 inhibitor resulted in a significant decrease in IL-17A production indicating that TLR9 is involved in this pathway. In human subjects, examining the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects showed a propensity for linearity that was not observed in controls. Our data thus indicates that EBV DNA itself acts as a modulator of the Th17 compartment as well as that of regulatory T cell mechanisms. The involvement of TLR9 in the EBV DNA-triggered induction of IL-17A suggests therapeutic targeting of this endosomal receptor in EBV positive subjects with an autoimmune flare-up or possibly for prophylactic purposes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Viral / immunology*
  • Female
  • Herpesvirus 4, Human / immunology*
  • Interleukin-17 / immunology*
  • Mice
  • Mice, Inbred BALB C
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / antagonists & inhibitors
  • Toll-Like Receptor 9 / immunology*

Substances

  • DNA, Viral
  • Il17a protein, mouse
  • Interleukin-17
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9

Grants and funding

This study was supported by a grant from the Lebanese National Council for Scientific Research (CNRS-L). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.