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 κB (NF-κB), NFAT, and mTORC1 activity. Weak BCR engagement induces apoptosis by failing to activate NF-κB-driven anti-apoptotic gene expression. Stronger signals that trigger more robust Ca2+ signals promote NF-κB-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.
Original language | American English |
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Article number | 107474 |
Journal | Cell Reports |
Volume | 31 |
Issue number | 2 |
DOIs | |
State | Published - 14 Apr 2020 |
Keywords
- Bcl-xL
- CD40
- NFAT
- Orai1
- STIM1
- apoptosis
- c-Myc
- c-Rel
- mTORC1
- nuclear factor kappa B
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology