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BCR-Induced Ca 2+ Signals Dynamically Tune Key Checkpoints that Control the Survival, Metabolic Reprogramming, and Proliferation of Naïve B Cells

Authors :
Igor E. Brodksy
Youhai H. Chen
Michael J. May
Xiaohong Liu
Bruce D. Freedman
Christopher J. Lengner
Michael P. Cancro
Arpita Myles
Satabdi Nandi
Corbett T. Berry
Uri Hershberg
Source :
SSRN Electronic Journal.
Publication Year :
2019
Publisher :
Elsevier BV, 2019.

Abstract

B cell receptor engagement induces naive B cells to differentiate and perform critical immune-regulatory functions. Acquisition of functional specificity requires that each cell navigate through checkpoints that control its survival, cell cycle entry, and proliferative expansion. Dynamic changes in BCR-induced calcium concentration critically regulate these checkpoints. Here we establish that variations in BCR signaling strength are encoded as calcium signals that tune each cell’s fate by dynamically regulating NF-κB, NFAT, and mTORC1 dependent control of gene expression. We find that weak BCR signaling induces apoptosis by failing to activate c-Rel-dependent Bcl-xL expression. Progressively stronger signals, which generate quantitatively distinct calcium signals, are required to promote c-Rel dependent survival, drive metabolic reprogramming, initiate cell cycle entry, and drive proliferation via NFAT-, mTORC1-, and Myc-dependent mechanisms. Finally, we establish the mechanism by which CD40 and PAMP costimulation decrease the calcium threshold for these key steps of B cell activation and differentiation. As altered BCR signaling is linked to autoimmunity and B cell malignancies, our results have important implications for understanding the pathogenesis of aberrant B cell differentiation.

Details

ISSN :
15565068
Database :
OpenAIRE
Journal :
SSRN Electronic Journal
Accession number :
edsair.doi...........d555d365e51f85fdeacec5688c449af0
Full Text :
https://doi.org/10.2139/ssrn.3443857