Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response

CM Fang, S Roy, E Nielsen, M Paul, R Maul, A Paun… - Genes & …, 2012 - nature.com
CM Fang, S Roy, E Nielsen, M Paul, R Maul, A Paun, F Koentgen, FM Raval…
Genes & Immunity, 2012nature.com
IRF-5 is a transcription factor activated by toll like receptor (TLR) 7 and TLR9 during innate
immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines.
Most importantly, a genetic variation in the IRF-5 gene shows a strong association with
autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have
attenuated IgG2a/c responses to T-cell-dependent and-independent antigens and to
polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID …
Abstract
IRF-5 is a transcription factor activated by toll like receptor (TLR) 7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell-dependent and-independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5−/− B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5−/− B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5−/− B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching.
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