RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production

PLoS Pathog. 2017 Nov 29;13(11):e1006738. doi: 10.1371/journal.ppat.1006738. eCollection 2017 Nov.

Abstract

Follicular T helper cells (TFH) are fundamental in orchestrating effective antibody-mediated responses critical for immunity against viral infections and effective vaccines. However, it is unclear how virus infection leads to TFH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) drives TFH formation via crosstalk of RIG-I-like receptor (RLR) RIG-I and MDA5 with type I Interferon (IFN) signaling. DENV infection leads to RLR-dependent IKKε activation, which phosphorylates IFNα/β receptor-induced STAT1 to drive IL-27 production via the transcriptional complex ISGF3. Inhibiting RLR activation as well as neutralizing antibodies against IL-27 prevented TFH formation. DENV-induced CXCR5+PD-1+Bcl-6+ TFH cells secreted IL-21 and activated B cells to produce IgM and IgG. Notably, RLR activation by synthetic ligands also induced IL-27 secretion and TFH polarization. These results identify an innate mechanism by which antibodies develop during viral disease and identify RLR ligands as potent adjuvants for TFH-promoting vaccination strategies.

MeSH terms

  • Antibodies, Viral / immunology*
  • Antibody Formation
  • B-Lymphocytes / immunology
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology
  • Dendritic Cells / immunology
  • Dengue / genetics
  • Dengue / immunology*
  • Dengue / virology
  • Dengue Virus / physiology*
  • Humans
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Interleukin-27 / genetics
  • Interleukin-27 / immunology
  • Interleukins / genetics
  • Interleukins / immunology
  • Lymphocyte Activation
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Antibodies, Viral
  • Interleukin-27
  • Interleukins
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1
  • interleukin-21

Grant support

This work was supported by the Netherlands Organization for Scientific Research http://www.nwo.nl/ (TBHG, NWO VICI 918.10.619) and the European Research Council https://erc.europa.eu/ (TBHG, Advanced grant 670424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.