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: PublishedMore...
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
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