Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation

Immunity. 2006 Aug;25(2):225-36. doi: 10.1016/j.immuni.2006.07.009.


Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4(-/-) B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4(-/-) B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Differentiation*
  • Cell Proliferation
  • Cells, Cultured
  • Cytidine Deaminase / metabolism
  • DNA / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Genome / genetics
  • Immunoglobulin Class Switching / immunology*
  • Immunoglobulin G / immunology
  • Immunoglobulin Isotypes / genetics
  • Immunoglobulin Isotypes / immunology
  • Interferon Regulatory Factors / deficiency
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology*
  • Interferon Regulatory Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Plasma Cells / cytology*
  • Plasma Cells / immunology*
  • Positive Regulatory Domain I-Binding Factor 1
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • Immunoglobulin G
  • Immunoglobulin Isotypes
  • Interferon Regulatory Factors
  • Prdm1 protein, mouse
  • Repressor Proteins
  • Transcription Factors
  • interferon regulatory factor-4
  • DNA
  • Positive Regulatory Domain I-Binding Factor 1
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase