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

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.