BCR-Induced Ca2+ Signals Dynamically Tune Survival, Metabolic Reprogramming, and Proliferation of Naive B Cells.

ABSTRACT: B cell receptor (BCR) engagement induces naive B cells to differentiate and perform critical immune-regulatory functions. Acquisition of functional specificity requires that a cell survive, enter the cell cycle, and proliferate. We establish that quantitatively distinct Ca2+ signals triggered by variations in the extent of BCR engagement dynamically regulate these transitions by controlling nuclear factor ?B (NF-?B), NFAT, and mTORC1 activity. Weak BCR engagement induces apoptosis by failing to activate NF-?B-driven anti-apoptotic gene expression. Stronger signals that trigger more robust Ca2+ signals promote NF-?B-dependent survival and NFAT-, mTORC1-, and c-Myc-dependent cell-cycle entry and proliferation. Finally, we establish that CD40 or TLR9 costimulation circumvents these Ca2+-regulated checkpoints of B cell activation and proliferation. As altered BCR signaling is linked to autoimmunity and B cell malignancies, these results have important implications for understanding the pathogenesis of aberrant B cell activation and differentiation and therapeutic approaches to target these responses.

SUBMITTER: Berry CT 

PROVIDER: S-EPMC7301411 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature