ynamic%20NF%EF%81%ABB_cRel%20phases%20B-cells%20from%20proliferation%20to%20plasma%20cell%20differentiation.pdf (7.53 MB)
A Regulatory Circuit Controlling the Dynamics of NF?B cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation
journal contribution
posted on 2023-06-21, 06:01 authored by Koushik Roy, Simon MitchellSimon Mitchell, Yi Liu, Sho Ohta, Yu-sheng Lin, Marie Oliver Metzig, Stephen L. Nutt, Alexander HoffmannHumoral immunity depends on efficient activation of B-cells and their subsequent differentiation to antibody secreting cells (ASCs). Nuclear factor ?B (NF?B) cRel is critical for B-cell proliferation, but incorporating its known regulatory interactions into a mathematical model of the ASC differentiation circuit leads to the prediction that cRel inhibits ASC generation. Indeed, experimental studies revealed that cRel is dynamically repressed during ASC differentiation, and that ectopic cRel expression blocks ASC differentiation by inhibiting Blimp1. Conversely, Blimp1 inhibits cRel expression by binding the Rel locus. Including this bi-stable circuit of mutual cRel- Blimp1 antagonism into a multi-scale model revealed that dynamic repression of NF?B/cRel controls the switch from B-cell proliferation to ASC generation phases and hence the respective cell population dynamics. Our studies provide a mechanistic explanation of how dysregulation of this bi-stable circuit may result in pathologic B-cell population phenotypes, and thus offer new avenues for diagnostic stratification and treatment.
History
Publication status
- Published
File Version
- Accepted version
Journal
ImmunityISSN
1074-7613Publisher
ElsevierExternal DOI
Issue
3Volume
50Page range
616-628.e6Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-06-17First Open Access (FOA) Date
2020-03-05First Compliant Deposit (FCD) Date
2019-06-17Usage metrics
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