Kurata-Sato, I. | bioRxiv Science

bioRxiv2025

IL-21-STAT3 axis negatively regulates LAIR1 expression in B cells

LAIR1 is an inhibitory receptor broadly expressed on human immune cells, including B cells. LAIR1 has been shown to modulate BCR signaling, however, it is still unclear whether its suppressive activity can be a negative regulator for autoreactivity. In this study, we demonstrate the LAIR1 expression profile on human B cells and prove its regulatory function and relationships to B cell autoreactivity. We show that both the frequency and level of LAIR1 expression decreases during B cell differentiation. LAIR1 expressing (LAIR1+) switched memory (SWM) B cells have a transcriptional profile less differentiated toward a plasma cell (PC) phenotype, harbor more autoreactive B cells and exhibit less PC differentiation in vitro than the LAIR1 negative (LAIR1-) counterpart. These data suggests that LAIR1 functions as a B cell tolerance checkpoint. We confirm previous data showing that patients with systemic lupus erythematosus (SLE) express less LAIR1 on B cells, implying a breakdown of the checkpoint, consistent with the enhanced PC differentiation seen in SLE. We further demonstrate that LAIR1 expression is down-regulated through the IL-21/STAT3 pathway which is known to be upregulated in SLE. These data suggest therapeutic targets that might decrease the aberrant PC differentiation observed in SLE.

immunology↗

bioRxiv2023

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 7 and 9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. Engagement of the 4 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.

immunology↗