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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

56 Pages Posted: 28 Aug 2019 Publication Status: Published

See all articles by Corbett Berry

Corbett Berry

University of Pennsylvania - Department of Pathobiology

Xiaohong Liu

University of Pennsylvania - Department of Pathobiology

Arpita Myles

University of Pennsylvania - Department of Pathology and Lab Medicine

Satabdi Nandi

University of Pennsylvania - Department of Biomedical Sciences

Youhai H. Chen

University of Pennsylvania - Department of Pathology

Uri Hershberg

Drexel University - School of Biomedical Engineering

Igor E. Brodksy

University of Pennsylvania - Department of Pathobiology

Michael P. Cancro

University of Pennsylvania - Department of Pathology and Lab Medicine

Christopher J. Lengner

University of Pennsylvania - Department of Biomedical Sciences

Michael J. May

University of Pennsylvania - Department of Biomedical Sciences

Bruce D. Freedman

University of Pennsylvania - Department of Pathobiology

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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.

Keywords: B lymphocyte, BCR signal strength, CD40, Calcium, Orai, STIM, c-Myc, Bcl-xL, proliferation, apoptosis, metabolic reprogramming, mTORC1, Nuclear Factor Kappa Beta, c-Rel, p65, NFAT, Follicular B cell, survival, cell cycle, Calcineurin, Akt, Foxo1, phospho-S

Suggested Citation

Berry, Corbett and Liu, Xiaohong and Myles, Arpita and Nandi, Satabdi and Chen, Youhai H. and Hershberg, Uri and Brodksy, Igor E. and Cancro, Michael P. and Lengner, Christopher J. and May, Michael J. and Freedman, Bruce D., BCR-Induced Ca 2+ Signals Dynamically Tune Key Checkpoints that Control the Survival, Metabolic Reprogramming, and Proliferation of Naïve B Cells (August 27, 2019). Available at SSRN: https://ssrn.com/abstract=3443857 or http://dx.doi.org/10.2139/ssrn.3443857
This version of the paper has not been formally peer reviewed.

Corbett Berry

University of Pennsylvania - Department of Pathobiology ( email )

Philadephia, PA
United States

Xiaohong Liu

University of Pennsylvania - Department of Pathobiology

Philadephia, PA
United States

Arpita Myles

University of Pennsylvania - Department of Pathology and Lab Medicine

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Satabdi Nandi

University of Pennsylvania - Department of Biomedical Sciences

United States

Youhai H. Chen

University of Pennsylvania - Department of Pathology

United States

Uri Hershberg

Drexel University - School of Biomedical Engineering

3141 Chestnut St
Philadelphia, PA 19104
United States

Igor E. Brodksy

University of Pennsylvania - Department of Pathobiology

Philadephia, PA
United States

Michael P. Cancro

University of Pennsylvania - Department of Pathology and Lab Medicine ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Christopher J. Lengner

University of Pennsylvania - Department of Biomedical Sciences

United States

Michael J. May

University of Pennsylvania - Department of Biomedical Sciences

United States

Bruce D. Freedman (Contact Author)

University of Pennsylvania - Department of Pathobiology ( email )

Philadephia, PA
United States

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