An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling

Mol Syst Biol. 2011 May 24:7:495. doi: 10.1038/msb.2011.25.

Abstract

The B-lymphocyte lineage is a leading system for analyzing gene regulatory networks (GRNs) that orchestrate distinct cell fate transitions. Upon antigen recognition, B cells can diversify their immunoglobulin (Ig) repertoire via somatic hypermutation (SHM) and/or class switch DNA recombination (CSR) before differentiating into antibody-secreting plasma cells. We construct a mathematical model for a GRN underlying this developmental dynamic. The intensity of signaling through the Ig receptor is shown to control the bimodal expression of a pivotal transcription factor, IRF-4, which dictates B cell fate outcomes. Computational modeling coupled with experimental analysis supports a model of 'kinetic control', in which B cell developmental trajectories pass through an obligate transient state of variable duration that promotes diversification of the antibody repertoire by SHM/CSR in direct response to antigens. More generally, this network motif could be used to translate a morphogen gradient into developmental inductive events of varying time, thereby enabling the specification of distinct cell fates.

Publication types

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

MeSH terms

  • Animals
  • Antibody Diversity / genetics
  • Antibody Diversity / immunology*
  • Antigens / genetics
  • Antigens / immunology
  • Antigens / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Gene Regulatory Networks*
  • Genes, Immunoglobulin*
  • Immunoglobulin Class Switching / genetics
  • Interferon Regulatory Factors* / genetics
  • Interferon Regulatory Factors* / immunology
  • Interferon Regulatory Factors* / metabolism
  • Mathematical Computing
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Recombination, Genetic / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Somatic Hypermutation, Immunoglobulin / genetics
  • Systems Biology / methods

Substances

  • Antigens
  • Interferon Regulatory Factors
  • interferon regulatory factor-4