1. A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation
- Author
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Roy, Koushik, Mitchell, Simon, Liu, Yi, Ohta, Sho, Lin, Yu-sheng, Metzig, Marie Oliver, Nutt, Stephen L, and Hoffmann, Alexander
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Stem Cell Research ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Generic health relevance ,Animals ,Antibody-Producing Cells ,B-Lymphocytes ,Cell Differentiation ,Cell Line ,Cell Proliferation ,Female ,Gene Expression Regulation ,HEK293 Cells ,Humans ,Immunity ,Humoral ,Lymphocyte Activation ,Mice ,Mice ,Inbred C57BL ,NF-kappa B ,B cells ,Blimp1 ,NFκB ,antibody-secreting cells ,differentiation ,multi-scale model ,mutual antagonism ,proliferation - Abstract
Humoral immunity depends on efficient activation of B cells and their subsequent differentiation into antibody-secreting cells (ASCs). The transcription factor NFκB cRel is critical for B cell proliferation, but incorporating its known regulatory interactions into a mathematical model of the ASC differentiation circuit prevented ASC generation in simulations. Indeed, experimental ectopic cRel expression blocked ASC differentiation by inhibiting the transcription factor Blimp1, and in wild-type (WT) cells cRel was dynamically repressed during ASC differentiation by Blimp1 binding the Rel locus. Including this bi-stable circuit of mutual cRel-Blimp1 antagonism into a multi-scale model revealed that dynamic repression of 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 might result in pathologic B cell population phenotypes and thus offer new avenues for diagnostic stratification and treatment.
- Published
- 2019