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

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 summary Strong antibody production is critical for effective immune responses against viral infections and is a primary factor in the development of successful vaccines. However, it is unclear how virus infection leads to effective antibody responses. Dengue virus (DENV) is known to induce potent antibody production, although the underlying mechanism is poorly understood. Dendritic cells (DCs) are professional sentinels of the immune system and crucial for induction of immune responses. Here we show that DENV infection of human DCs leads to robust antibody production by inducing a specific T helper cell type (also called follicular T helper or TFH) that specializes in stimulating antibody production by B cells. Our data show that DENV replication triggers a viral detection system consisting of sensors RIG-I and MDA5, which specifically induce factors such as IL-27 that are essential for TFH induction. Our data demonstrate that this viral detection system is especially powerful to induce antibody production. Indeed, synthetic molecules that trigger this viral detection mechanism induced superior antibody production compared to other activation signals. Thus, we have identified a viral detection mechanism that leads to strong antibody production and its importance in DENV infection as well as its potential in vaccinations.