title: Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.
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.
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: C-M
authors.initials: CM
authors.lastname: Fang
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.forename: E
authors.initials: E
authors.lastname: Nielsen
authors.forename: M
authors.initials: M
authors.lastname: Paul
authors.forename: R
authors.initials: R
authors.lastname: Maul
authors.forename: A
authors.initials: A
authors.lastname: Paun
authors.forename: F
authors.initials: F
authors.lastname: Koentgen
authors.forename: F M
authors.initials: FM
authors.lastname: Raval
authors.forename: E
authors.initials: E
authors.lastname: Szomolanyi-Tsuda
authors.forename: P M
authors.initials: PM
authors.lastname: Pitha
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D003564:Cytidine Deaminase / Q000378:metabolism; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D056724:Immunity, Humoral; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000098815:T-bet Transcription Factor; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D000941:Antigens; D003564:Cytidine Deaminase; D051740:Ikaros Transcription Factor; D007074:Immunoglobulin G; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C498178:Irf5 protein, mouse; C497238:Zfpn1a1 protein, mouse