A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation
| Autor: | Koushik Roy, Alexander Hoffmann, Sho Ohta, Stephen L. Nutt, Yi Liu, Marie Oliver Metzig, Yu-sheng Lin, Simon Mitchell |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Inbred C57BL Lymphocyte Activation Mice 0302 clinical medicine Plasma cell differentiation 2.1 Biological and endogenous factors Immunology and Allergy Aetiology B-Lymphocytes education.field_of_study NF-kappa B Humoral antibody-secreting cells Cell Differentiation differentiation Phenotype Cell biology Infectious Diseases medicine.anatomical_structure 030220 oncology & carcinogenesis Female multi-scale model Blimp1 proliferation 1.1 Normal biological development and functioning Immunology Population Biology mutual antagonism Article Cell Line 03 medical and health sciences Underpinning research medicine Animals Humans Antibody-Producing Cells education Psychological repression Transcription factor B cell Cell Proliferation B cells Immunity Stem Cell Research Immunity Humoral Mice Inbred C57BL HEK293 Cells 030104 developmental biology Gene Expression Regulation Humoral immunity Generic health relevance NFκB |
| Zdroj: | Immunity, vol 50, iss 3 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2019.02.004 |
| Popis: | Humoral immunity depends on efficient activation of B-cells and their subsequent differentiation to 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, in experimental studies cRel was dynamically repressed during ASC differentiation, and ectopic cRel expression blocked ASC differentiation by inhibiting the transcription factor Blimp1. Conversely, after Blimp1 is induced in ASCs, it represses cRel 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 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 present avenues for diagnostic stratification and treatment. SUGGESTED REVISION: Precise regulation of transcription factor NFkB mediates efficient activation of B-cells and their subsequent differentiation to antibody secreting cells (ASCs). To obtain a quantitative understanding of how specific NFκB dimers control ASC differentiation, we developed a mathematical model that investigated NFkB subunits cRel and RelA as distinct regulators. This model predicted that cRel inhibits ASC generation. Indeed, cRel was dynamically repressed during ASC differentiation, and ectopic cRel expression blocked ASC differentiation by inhibiting the transcription factor Blimp1. Conversely, Blimp1 inhibited 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 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 present avenues for diagnostic stratification and treatment. |
| Databáze: | OpenAIRE |
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