The impact of type I interferon driven cytokines on the plasmablast response to viral pathogens

Abstract

Abstract The plasmablast B cell (PB) response to viruses provides the first wave of functional virus specific antibodies. PBs may undergo immunoglobulin class switch recombination (CSR), giving these antibodies a diverse array of properties and functions that contribute to their mechanisms of viral clearance. Dendritic cells (DCs) can prime a PB response through native antigen production, cell surface interactions, and soluble mediators including cytokines. Additionally, we know that type I interferon (IFN) has dynamic regulatory functions by inducing expression of interferon stimulated genes (ISGs) in addition to having potent anti-proliferative and anti-viral effects. We hypothesize that signaling of type I IFN inhibits the PB response induced by virial infection by impacting the cytokine milieu, magnitude and diversity of the PB response, and mechanisms of antibody mediated protection. As DCs are potent producers of type I IFN and mediate direct interactions with B cells, we employed a DC specific knockout of Ifnar1 from the type I IFN receptor, CD11c Cre X Ifnarfl/fl, to challenge our hypothesis. Overall, we show that ablation of type I IFN signaling followed by infection with Zika virus (ZIKV) results in an increase in PB frequency in lymphoid tissue, increase in CSR, and potent increase in the neutralization capacity of polyclonal sera. The results of these studies can be leveraged to increase immunogenicity of mRNA and attenuated vaccines while targeting for a quicker antibody response.