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

Joris K Sprokholt; Tanja M Kaptein; John L van Hamme; Ronald J Overmars; Sonja I Gringhuis; Teunis B H Geijtenbeek

doi:10.1371/journal.ppat.1006738

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.

Authors

Joris K Sprokholt^{1

2}, Tanja M Kaptein^{1

2}, John L van Hamme^{1

2}, Ronald J Overmars^{1

2}, Sonja I Gringhuis^{1

2}, Teunis B H Geijtenbeek^{1

2}

Affiliations

¹ Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
² Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands.

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
Receptors, Immunologic
T-Lymphocytes, Helper-Inducer / immunology*

Substances

Antibodies, Viral
Interleukin-27
Interleukins
Receptors, Immunologic
RIGI protein, human
IFIH1 protein, human
DEAD Box Protein 58
Interferon-Induced Helicase, IFIH1
interleukin-21

Grants and funding

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.