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

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

Author information

1
Signaling 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.
2
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
3
Signaling 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. Electronic address: ahoffmann@ucla.edu.

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.

KEYWORDS:

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

PMID:
30850343
PMCID:
PMC6955201
DOI:
10.1016/j.immuni.2019.02.004
[Indexed for MEDLINE]
Free PMC Article

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