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

Immunity. 2019 Mar 19;50(3):616-628.e6. doi: 10.1016/j.immuni.2019.02.004. Epub 2019 Mar 5.


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.

Keywords: B cells; Blimp1; NFκB; antibody-secreting cells; differentiation; multi-scale model; mutual antagonism; proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody-Producing Cells / immunology
  • B-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Cell Line
  • Cell Proliferation / physiology*
  • Female
  • Gene Expression Regulation / immunology
  • HEK293 Cells
  • Humans
  • Immunity, Humoral / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / immunology*


  • NF-kappa B