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Nat Immunol. 2015 Dec;16(12):1274-81. doi: 10.1038/ni.3287. Epub 2015 Oct 5.

Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8.

Author information

1
Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Abstract

Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. Genomic analysis revealed concentration-dependent actions of IRF4 and IRF8 in regulating distinct gene-expression programs. Stochastic modeling suggested that the double-negative feedback was sufficient to initiate bifurcation of the B cell developmental trajectories.

PMID:
26437243
DOI:
10.1038/ni.3287
[Indexed for MEDLINE]

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