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

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 var...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 31; no. 2; p. 107474
Main Authors: Berry, Corbett T., Liu, Xiaohong, Myles, Arpita, Nandi, Satabdi, Chen, Youhai H., Hershberg, Uri, Brodsky, Igor E., Cancro, Michael P., Lengner, Christopher J., May, Michael J., Freedman, Bruce D.
Format: Journal Article
Language:English
Published: Elsevier Inc 14.04.2020
Subjects:
apoptosis
Bcl-xL
c-Myc
c-Rel
CD40
mTORC1
NFAT
nuclear factor kappa B
Orai1
STIM1
CD40
Bcl-xL
STIM1
c-Myc
nuclear factor kappa B
c-Rel
Orai1
apoptosis
mTORC1
NFAT
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Description
Summary: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. [Display omitted] •BCR signal strength is encoded as quantitatively distinct intracellular Ca2+ signals•Ca2+ dynamics are decoded by NF-κB, NFAT, and mTORC1 to drive cell fates•BCR-induced Ca2+ signals are required for maximal B cell survival and proliferation•CD40 compensates for weak BCR/Ca2+ signals to rescue NF-κB- and mTORC1-dependent fates Berry et al. establish that variations in the strength of BCR engagement are encoded as quantitatively distinct calcium signals that tune B cell fates by dynamically regulating NF-κB, NFAT, and mTORC1 activity. Targeting calcium signaling may thereby serve as an effective treatment strategy for regulating normal and pathological B cell activation.
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AUTHOR CONTRIBUTIONS
Conceptualization, C.T.B. and B.D.F.; Methodology, C.T.B. and B.D.F.; Investigation, C.T.B., X.L., A.M., S.N., and B.D.F.; Writing – Original Draft, C.T.B., M.J.M., and B.D.F.; Writing – Review & Editing, C.T.B, Y.H.C., I.E.B., M.P.C., C.J.L., and B.D.F.; Funding Acquisition, B.D.F. and M.J.M.; Resources, B.D.F., Y.H.C., I.E.B., M.P.C., C.J.L., and M.J.M.; Supervision, B.D.F.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.03.038