Critical role of IRF-5 in regulation of B-cell differentiation

Chunyang Lien, Chee Mun Fang, David Huso, Ferenc Livak, Runqing Lu, Paula M. Pitha

Research output: Contribution to journalArticlepeer-review

Abstract

IFN-regulatory factor 5 (IRF-5), a member of the IRF family, is a transcriptionfactor that has a key role in the induction of the antiviral and inflammatory response. When compared with C57BL/6 mice, Irf5-/- mice show higher susceptibility to viral infection and decreased serum levels of type I IFN and the inflammatory cytokines IL-6 and TNF-α. Here, we demonstrate that IRF-5 is involved in B-cell maturation and the stimulation of Blimp-1 expression. The Irf5-/- mice develop an age-related splenomegaly, associated with a dramatic accumulation of CD19+B220- B cells and a disruption of normal splenic architecture. Splenic B cells from Irf5-/- mice also exhibited a decreased level ofplasma cells. TheCD19+ Irf5-/- B cells showa defect inToll-like receptor (TLR) 7- andTLR9-induced IL-6 production, andthe aged Irf5-/- mice have decreased serum levels of natural antibodies; however, the antigen-specific IgG1 primary response was already dependent in IRF-5 in young mice, although the IgM response was not. Analysis of the profile of transcription factors associated with plasma cell differentiationshows down-regulationofBlimp-1 expression, a master regulator of plasma cell differentiation, which can be reconstituted with ectopic IRF-5. IRF-5 stimulates transcription of the Prdm1 gene encoding Blimp-1 and binds to the IRF site in the Prdm1 promoter. Collectively, these results reveal that the age-related splenomegaly in Irf5-/- mice is associated with an accumulation of CD19 +B220- B cells with impaired functions and show the role of IRF-5 i the direct regulation of the plasma cell commitment factor Blimp-1 annd in B-cell terminal differentiation.

Original languageEnglish (US)
Pages (from-to)4664-4668
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number10
DOIs
StatePublished - Mar 9 2010

Keywords

  • Antigenic response
  • B-cell development
  • Blimp-1
  • IRF-5
  • Toll-like receptors

ASJC Scopus subject areas

  • General

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