A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation.
Immunity
; 50(3): 616-628.e6, 2019 03 19.
Article
em En
| MEDLINE
| ID: mdl-30850343
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
/
Diferenciação Celular
/
NF-kappa B
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Proliferação de Células
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Immunity
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos