Vagus nerve stimulation limits the germinal center B cell response via CD4+ T cell-derived acetylcholine
Neural signals are known to contribute to immune regulation and modulation of the innate immune response downstream of the vagus nerve has been well studied. The effects of vagus nerve activity on antibody production, however, have been largely unexplored. Here we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of vagal activation on T-dependent B cell responses. We observed lower titers of high-affinity serum IgG and fewer antigen-specific germinal center (GC) B cells in the spleen. GC B cells from chronic VNS mice expressed more active caspase-3 and exhibited an altered gene expression profile suggesting increased susceptibility to apoptosis and impaired maturation. Follicular dendritic cell (FDC) cluster dispersal and altered FDC gene expression suggested poor FDC function. These alterations were diminished in the absence of a subset of acetylcholine-producing CD4+ T cells. In vitro studies revealed that a7 and a9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. Engagement of the a4 nAChR subunit on B cells impaired Akt phosphorylation, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed, at least in part, to the effect of acetylcholine on B cell intrinsic pathways, resulting in hindered B cell survival and maturation and leading to an alteration in FDC function. Our findings identify a potential therapeutic target to prevent immunosuppression in conditions associated with increased vagal activity. Overall design: NP-specific activated B cell of chronic vagus nerve stimulation and sham mice immunized with NP-CGG were isolated from the spleens by fluorescence-activated cell sorting (FACS) according to B220 and GL7 signals and binding to NP antigen and analyzed using scRNAseq.