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

Follicular T helper cells (T-FH) 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 T-FH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) drives T-FH 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 IKK epsilon activation, which phosphorylates IFN alpha/beta 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 T-FH formation. DENV-induced CXCR5 (+) PD-1 (+) Bcl-6 (+) T-FH 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 T-FH polarization. These results identify an innate mechanism by which antibodies develop during viral disease and identify RLR ligands as potent adjuvants for T-FH-promoting vaccination strategies.