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.
Highlights
Dengue virus is a global mosquito-transmitted pathogen that infects 400 mln people annually [1]
We show that dengue virus (DENV) infection of human dendritic cells (DCs) leads to robust antibody production by inducing a specific T helper cell type 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 induce factors such as IL-27 that are essential for TFH induction
Summary
Dengue virus is a global mosquito-transmitted pathogen that infects 400 mln people annually [1]. Antibodies play a dual role in DENV pathology as neutralizing highaffinity antibodies are protective while cross-reacting antibodies can possibly enhance disease of heterologous DENV strains via antibody-dependent enhancement of infection [2]. It is unclear how antibodies are induced upon DENV infection. TFH cells are critical for the formation and maintenance of GCs, and induce B cell proliferation and Ig isotype class switching by producing IL-21. TFH cells selectively stimulate high-affinity B cell entry into GCs to promote effective antibody-mediated responses [3,4,5]. DCs are essential for TFH differentiation from naïve CD4+ T cells and previously we have shown that in humans IL-27 is pivotal for TFH formation while IL-6 enhances TFH formation in response to fucosylated parasitic/bacterial ligands [7]
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