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

Genes & Immunity volume 13, pages 421–430 (2012)Cite this article

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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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Acknowledgements

We wish to acknowledge the generosity of Drs T Mak, E Lien and T Taniguchi for the gift of Irf5−/− N6, Irf5−/− N10 and Irf7−/− mice, respectively, and M Diamond for sharing with us his observation on Dock2 mutation before publication. We also thank Drs P Gerhardt for her advice on the CSR protocols, K Gergopoulos and R Lu for the gift of Ikaros expression plasmids and IRF-5 retroviral vector, respectively. and S Vogel for the gift of anti STAT1 antibodies and critical comments on the manuscript. The advice of Jacqui Watts on mice mating and help from Y Woo and H Lee with mice genotyping is greatly appreciated. The work was supported by NIH AI067632 and 3RO1-AI1067632-05S1 grants to PMP and RO1 CA 66644 and NIH AI 073651 grants to EST.

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  1. C-M Fang and S Roy: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Biology, Johns Hopkins University, Baltimore, MD, USA

    C-M Fang, S Roy, E Nielsen, M Paul & P M Pitha

  2. Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    R Maul

  3. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, National Institute of Health, Bethesda, MD, USA

    A Paun

  4. Ozgene, Perth, WA, Australia

    F Koentgen

  5. Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA, USA

    F M Raval & E Szomolanyi-Tsuda

  6. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    P M Pitha

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Correspondence to P M Pitha.

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FK is a director at Ozgene, Ltd. The other authors have no conflict of interest to declare.

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Fang, CM., Roy, S., Nielsen, E. et al. Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response. Genes Immun 13, 421–430 (2012). https://doi.org/10.1038/gene.2012.10

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