期刊
CELL REPORTS
卷 31, 期 2, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.03.038
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资金
- NIH [R56AI125415, RO1AI60921, R01HL096642, R01AR066567, AI128530]
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 kappa B (NF-kappa B), NFAT, and mTORC1 activity. Weak BCR engagement induces apoptosis by failing to activate NF-kappa B-driven anti-apoptotic gene expression. Stronger signals that trigger more robust Ca2+ signals promote NF-kappa 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.
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