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