A regulatory circuit controlling the dynamics of NFkappaB cRel transitions B cells from proliferation to plasma cell differentiation
- Author(s)
- Roy, K; Mitchell, S; Liu, Y; Ohta, S; Lin, YS; Metzig, MO; Nutt, SL; Hoffmann, A;
- Journal Title
- Immunity
- Publication Type
- Journal Article
- Abstract
- Humoral immunity depends on efficient activation of B cells and their subsequent differentiation into antibody-secreting cells (ASCs). The transcription factor NFkappaB 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.
- Publisher
- Cell Press
- Research Division(s)
- Immunology
- PubMed ID
- 30850343
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2019.02.004
- NHMRC Grants
- NHMRC/1054925, NHMRC/1058238,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-03-13 11:54:00
Last Modified: 2019-03-13 12:05:31