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

Koushik Roy1, Simon Mitchell1, Yi Liu1

  • 1Signaling Systems Laboratory, Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Immunity
|March 10, 2019
PubMed

Insights

The transcription factor NFκB cRel dynamically regulates B cell differentiation into antibody-secreting cells (ASCs). This study reveals how Blimp1-mediated repression of cRel controls B cell proliferation and ASC generation, offering insights into immune disorders.

Area of Science:

  • Immunology
  • Computational Biology
  • Molecular Biology

Background:

  • Humoral immunity relies on B cell activation and differentiation into antibody-secreting cells (ASCs).
  • The transcription factor NFκB cRel is crucial for B cell proliferation.
  • Previous models struggled to incorporate cRel's regulatory roles in ASC differentiation.

Purpose of the Study:

  • To investigate the role of NFκB cRel in B cell differentiation into ASCs.
  • To develop a mathematical model explaining the dynamic regulation of ASC generation.
  • To elucidate the mechanism by which cRel influences B cell population dynamics.

Main Methods:

  • Mathematical modeling of the B cell differentiation circuit.
  • Incorporation of cRel and Blimp1 regulatory interactions.
  • Simulations of B cell proliferation and ASC generation phases.
  • Analysis of bi-stable circuit dynamics and mutual antagonism between cRel and Blimp1.

Main Results:

  • Ectopic cRel expression inhibited ASC differentiation by blocking the transcription factor Blimp1.
  • In wild-type cells, Blimp1 dynamically repressed cRel during ASC differentiation.
  • A multi-scale model incorporating mutual cRel-Blimp1 antagonism revealed dynamic cRel repression controls the switch between B cell proliferation and ASC generation.
  • This dynamic repression governs cell population dynamics during humoral immune responses.

Conclusions:

  • Dynamic repression of NFκB cRel by Blimp1 is essential for timely ASC generation.
  • Dysregulation of the cRel-Blimp1 bi-stable circuit can lead to pathologic B cell phenotypes.
  • These findings offer potential diagnostic and therapeutic strategies for immune-related diseases.

Keywords:
B cellsBlimp1NFκBantibody-secreting cellsdifferentiationmulti-scale modelmutual antagonismproliferation

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