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

Noam Ben-Shalom, Elad Sandbank, Lilach Abramovitz, Hadas Hezroni, Talia Levine, Estherina Trachtenberg, Nadav Fogel, Michael Mor, Ron Yefet, Liat Stoler-Barak, David Hagin, Akiko Nakai, Masaki Noda, Kazuhiro Suzuki, Ziv Shulman, Shamgar Ben-Eliyahu*, Natalia T. Freund

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)66-82
Number of pages17
JournalBrain, Behavior, and Immunity
Volume113
DOIs
Publication statusPublished - Oct 2023

Funding

Funding Information: This study was funded by the Breakthrough Prize 2018, Tel Aviv University. N.T.F is funded by Israel Science Foundation grants #1422/18 , #3711/20 , and 3136/22 . We thank the Marguerite Stolz Research Fellowship. Figures: 1A, 3A, 4A, 6A, and graphical abstract were created using BioRender.com. Funding Information: We thank R. Weiss for initiating this project and I. Sanjuan for advice and help with the ex vivo boost immunization protocols. We thank the Technion Genomics Center for performing the mRNA sequencing and the analysis. We thank Michal Navon for helping with the PCR experiments. We thank Eden Reznikov for helping with the ELISA. We thank all the members of the Freund and Ben-Eliyahu labs for fruitful discussions and assistance with the mouse experiments. This study was funded by the Breakthrough Prize 2018, Tel Aviv University. N.T.F is funded by Israel Science Foundation grants #1422/18, #3711/20, and 3136/22. We thank the Marguerite Stolz Research Fellowship. Figures: 1A, 3A, 4A, 6A, and graphical abstract were created using BioRender.com. Publisher Copyright: © 2023 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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