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:https://doi.org/10.1371/journal.ppat.1006738

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

Research output: Contribution to journal › Article › Academic › peer-review

34 Citations (Scopus)

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

Original language	English
Pages (from-to)	e1006738
Journal	PLoS pathogens
Volume	13
Issue number	11
DOIs	https://doi.org/10.1371/journal.ppat.1006738
Publication status	Published - 2017

Access to Document

https://doi.org/10.1371/journal.ppat.1006738Licence: CC BY

https://pure.amc.nl/ws/files/15880292/Sprokholt_10.1371journal.ppat.1006738.pdfLicence: CC BY

Cite this

@article{da88abac92cf4e619fa627fd0b9085ce,

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

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",

author = "Sprokholt, {Joris K.} and Kaptein, {Tanja M.} and {van Hamme}, {John L.} and Overmars, {Ronald J.} and Gringhuis, {Sonja I.} and Geijtenbeek, {Teunis B. H.}",

year = "2017",

doi = "https://doi.org/10.1371/journal.ppat.1006738",

language = "English",

volume = "13",

pages = "e1006738",

journal = "PLoS pathogens",

issn = "1553-7366",

publisher = "Public Library of Science",

number = "11",

}

TY - JOUR

T1 - RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production

AU - Sprokholt, Joris K.

AU - Kaptein, Tanja M.

AU - van Hamme, John L.

AU - Overmars, Ronald J.

AU - Gringhuis, Sonja I.

AU - Geijtenbeek, Teunis B. H.

PY - 2017

Y1 - 2017

N2 - 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

AB - 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

U2 - https://doi.org/10.1371/journal.ppat.1006738

DO - https://doi.org/10.1371/journal.ppat.1006738

M3 - Article

C2 - 29186193

SN - 1553-7366

VL - 13

SP - e1006738

JO - PLoS pathogens

JF - PLoS pathogens

IS - 11

ER -