β2-adrenergic signaling promotes higher-affinity B cells and antibodies

Abstract

Stress-induced β2-adrenergic receptor (β2AR) activation in B cells increases IgG secretion; however, the impact of this activation on antibody affinity and the underlying mechanisms remains unclear. In the current study, we demonstrate that stress in mice following ovalbumin (OVA) or SARS-CoV-2 RBD immunization significantly increases both serum and surface-expressed IgG binding to the immunogen, while concurrently reducing surface IgG expression and B cell clonal expansion. These effects were abolished by pharmacological β2AR blocking or when the experiments were conducted in β2AR -/- mice. In the second part of our study, we used single B cell sorting to characterize the monoclonal antibodies (mAbs) generated following β2AR activation in cultured RBD-stimulated B cells from convalescent SARS-CoV-2 donors. Ex vivo β2AR activation increased the affinities of the produced anti-RBD mAbs by 100-fold compared to mAbs produced by the same donor control cultures. Consistent with the mouse experiments, β2AR activation reduced both surface IgG levels and the frequency of expanded clones. mRNA sequencing revealed a β2AR-dependent upregulation of the PI3K pathway and B cell receptor (BCR) signaling through AKT phosphorylation, as well as an increased B cell motility. Overall, our study demonstrates that stress-mediated β2AR activation drives changes in B cells associated with BCR activation and higher affinity antibodies.