A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation

Roy, Koushik, Mitchell, Simon, Liu, Yi, Ohta, Sho, Lin, Yu-sheng, Metzig, Marie Oliver, Nutt, Stephen L. and Hoffmann, Alexander (2019) A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation. Immunity, 50 (3). 616-628.e6. ISSN 1074-7613

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Abstract

Humoral 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.

Item Type: Article
Keywords: B cells; Blimp1; NFκB; antibody-secreting cells; differentiation; multi-scale model; mutual antagonism; proliferation
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine
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Depositing User: Gemma Hamilton
Date Deposited: 17 Jun 2019 10:53
Last Modified: 05 Mar 2020 02:00
URI: http://sro.sussex.ac.uk/id/eprint/84326

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