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Essential role of Id2 in negative regulation of IgE class switching

Nature Immunology volume 4, pages 25–30 (2003)Cite this article

Abstract

Serum concentrations of immunoglobulin E (IgE) in normal circumstances are kept much lower than those of other Ig isotypes to avoid allergic reactions. B cells lacking Id2 have increased E2A activity, which leads to specific enhancement of germline transcription of the immunoglobulin ε locus. As a consequence, Id2-deficient B cells undergo class switch recombination (CSR) to IgE at a much higher frequency than wild-type B cells. In contrast, Id2 is induced in wild-type B cells by transforming growth factor-β1 (TGF-β1) and suppresses IgE CSR. Our results provide evidence for the inhibitory and selective role of Id2 in IgE CSR in response to TGF-β1. Id2 might act as molecular safeguard to suppress IgE CSR to prevent serious complications such as allergic hypersensitivity during the normal course of immune responses.

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Figure 1: Enhanced IgE class switching in the spleen.
Figure 2: Enhanced IgE class switching in Id2−/− B cells.
Figure 3: Transactivation of the GLε promoter by E2A transcription factors.
Figure 4: Binding of the GLε promoter by E2A transcription factors.
Figure 5: Reintroduction of Id2 protein restores enhanced IgE class switching.
Figure 6: Id2 is induced by TGF-β1 in splenic B cells.
Figure 7: Inhibition of IgE CSR by TGF-β1 is mediated by Id2.

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References

  1. Corry, D.B. & Kheradmand, F. Induction and regulation of the IgE response. Nature 402, 18–23 (1999).

    Article  Google Scholar 

  2. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  Google Scholar 

  3. Lundgren, M. et al. Activation of the Ig germ-line γ1 promoter. Involvement of C/enhancer-binding protein transcription factors and their possible interaction with an NF-IL-4 site. J. Immunol. 153, 2983–2995 (1994).

    CAS  PubMed  Google Scholar 

  4. Delphin, S. & Stavnezer, J. Characterization of an interleukin 4 (IL-4) responsive region in the immunoglobulin heavy chain germline ε promoter: regulation by NF-IL-4, a C/EBP family member and NF-κB/p50. J. Exp. Med. 181, 181–192 (1995).

    Article  CAS  Google Scholar 

  5. Honjo, T., Kinoshita, K. & Muramatsu, M. Molecular mechanism of class switch recombination: Linkage with somatic hypermutation. Annu. Rev. Immunol. 20, 165–196 (2002).

    Article  CAS  Google Scholar 

  6. Lee, C.G. et al. Quantitative regulation of class switch recombination by switch region transcription. J. Exp. Med. 194, 365–374 (2001).

    Article  CAS  Google Scholar 

  7. Lutzker, S., Rothman, P., Pollock, R., Coffman, R. & Alt, F.W. Mitogen- and IL-4-regulated expression of germ-line Ig 2b transcripts: evidence for directed heavy chain class switching. Cell 53, 177–184 (1988).

    Article  CAS  Google Scholar 

  8. Zhang, J., Alt, F.W. & Honjo, T. Regulation of class switch recombination of the immunoglobulin heavy chain genes. in Immunoglobulin Genes (eds. Honjo, T. & Alt, F. W.) 235–265 (Academic Press, London, 1995).

    Chapter  Google Scholar 

  9. Kuhn, R., Rajewsky, K. & Muller, W. Generation and analysis of interleukin-4 deficient mice. Science 254, 707–710 (1991).

    Article  CAS  Google Scholar 

  10. Kopf, M. et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245–248 (1993).

    Article  CAS  Google Scholar 

  11. Takeda, K. et al. Essential role of STAT6 in IL-4 signalling. Nature 380, 627–630 (1996).

    Article  CAS  Google Scholar 

  12. Shimoda, K. et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted STAT6 gene. Nature 380, 630–633 (1996).

    Article  CAS  Google Scholar 

  13. Snapper, C.M., Finkelman, F.D. & Paul, W.E. Differential regulation of IgG1 and IgE synthesis by interleukin 4. J. Exp. Med. 167, 183–196 (1988).

    Article  CAS  Google Scholar 

  14. Jung, S., Siebenkotten, G. & Radbruch, A. Frequency of immunoglobulin E class switching is autonomously determined and independent of prior switching to other classes. J. Exp. Med. 179, 2023–2026 (1994).

    Article  CAS  Google Scholar 

  15. Purkerson, J.M. & Isakson, P.C. Independent regulation of DNA recombination and immunoglobulin (Ig) secretion during isotype switching to IgG1 and IgE. J. Exp. Med. 179, 1877–1883 (1994).

    Article  CAS  Google Scholar 

  16. Bottaro, A. et al. S region transcription per se promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process. EMBO J. 13, 665–674 (1994).

    Article  CAS  Google Scholar 

  17. Norton, J.D., Deed, R.W., Craggs, G. & Sablitzky, F. Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol. 8, 58–65 (1998).

    CAS  PubMed  Google Scholar 

  18. Yokota, Y. & Mori, S. Role of Id family proteins in growth control. J. Cell. Physiol. 190, 21–28 (2002).

    Article  CAS  Google Scholar 

  19. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).

    Article  CAS  Google Scholar 

  20. Kusunoki, T. et al. Th2 dominance and defective CD8+ dendritic cell subset in Id2-deficient mice. J. Allergy Clin. Immunnol. (in the press, 2003).

  21. Chu, C.C., Paul, W.E. & Max, E.E. Quantitation of immunoglobulin μ-γ 1 heavy chain switch region recombination by a digestion-circularization polymerase chain reaction method. Proc. Natl. Acad. Sci. USA 89, 6978–6982 (1992).

    Article  CAS  Google Scholar 

  22. Qiu, G. & Stavnezer, J. Overexpression of BSAP/Pax-5 inhibits switching to IgA and enhances switching to IgE in the 1.29 μ B cell line. J. Immunol. 161, 2906–2918 (1998).

    CAS  PubMed  Google Scholar 

  23. Harris, M.B. et al. Transcriptional repression of STAT6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iε transcription and immunoglobulin E switching. Mol. Cell. Biol. 19, 7264–7275 (1999).

    Article  CAS  Google Scholar 

  24. Kamogawa, Y. et al. A conditionally active form of STAT6 can mimic certain effects of IL-4. J. Immunol. 161, 1074–1077 (1998).

    CAS  PubMed  Google Scholar 

  25. Nosaka, T. et al. STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J. 18, 4754–4765 (1999).

    Article  CAS  Google Scholar 

  26. Ye, S.K. et al. Induction of germline transcription in the TCRγ locus by Stat5: implications for accessibility control by the IL-7 receptor. Immunity 11, 213–223 (1999).

    Article  CAS  Google Scholar 

  27. Quong, M.W., Harris, D.P., Swain, S.L. & Murre, C. E2A activity is induced during B-cell activation to promote immunoglobulin class switch recombination. EMBO J. 18, 6307–6318 (1999).

    Article  CAS  Google Scholar 

  28. Gauchat, J.F., Aversa, G., Gascan, H. & de Vries, J.E. Modulation of IL-4 induced germline ε RNA synthesis in human B cells by tumor necrosis factor-α, anti-CD40 monoclonal antibodies or transforming growth factor-β correlates with levels of IgE production. Int. Immunol. 4, 397–406 (1992).

    Article  CAS  Google Scholar 

  29. Shockett, P. & Stavnezer, J. Effect of cytokines on switching to IgA and α germline transcripts in the B lymphoma 1.29 μ. Transforming growth factor-β activates transcription of the unrearranged C α gene. J. Immunol. 147, 4374–4383 (1991).

    CAS  PubMed  Google Scholar 

  30. van Ginkel, F.W. et al. Partial IgA-deficiency with increased Th2-type cytokines in TGF-β1 knockout mice. J. Immunol. 163, 1951–1957 (1999).

    CAS  PubMed  Google Scholar 

  31. Kee, B.L., Rivera, R.R. & Murre, C. Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-β. Nature Immunol. 2, 242–247 (2001).

    Article  CAS  Google Scholar 

  32. Roberts, E.C., Deed, R.W., Inoue, T., Norton, J.D. & Sharrocks, A.D. Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding. Mol. Cell Biol. 21, 524–533 (2001).

    Article  CAS  Google Scholar 

  33. Urbanek, P., Wang, Z.Q., Fetka, I., Wagner, E.F. & Busslinger, M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell 79, 901–912 (1994).

    Article  CAS  Google Scholar 

  34. Wahl, S.M. Transforming growth factor β: the good, the bad, and the ugly. J. Exp. Med. 180, 1587–1590 (1994).

    Article  CAS  Google Scholar 

  35. Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  Google Scholar 

  36. Sugai, M., Kondo, S., Shimizu, A. & Honjo, T. Isolation of differentially expressed genes upon immunoglobulin class switching by a subtractive hybridization method using uracil DNA glycosylase. Nucleic Acids Res. 26, 911–918 (1998).

    Article  CAS  Google Scholar 

  37. Kinsella, T.M. & Nolan, G.P. Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. Hum. Gene Ther. 7, 1405–1413 (1996).

    Article  CAS  Google Scholar 

  38. Matsuda, E. et al. Targeting of Krüppel-associated box-containing zinc finger proteins to centromeric heterochromatin. Implication for the gene silencing mechanisms. J. Biol. Chem. 276, 14222–14229 (2001).

    Article  CAS  Google Scholar 

  39. Hara, E., Hall, M. & Peters, G. Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors. EMBO J. 16, 332–342 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to K. Ikuta for discussions, H. Karasuyama for X63mIL3, A. Kudo for mPax5 expression plasmid, T. Kitamura for pMX-IRESGFP plasmid and G. P. Nolan for Phoenix Eco cells. We thank T. Ofuji for technical assistance. Supported in part by Grants-in-Aid for Scientific Research including ones on Priority Areas 'Genome Biology' (13206035, 14014220) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Center for Molecular Biology and Genetics, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, 606-8507, Kyoto, Japan

    Manabu Sugai, Hiroyuki Gonda, Tomoya Katakai & Akira Shimizu

  2. Translational Research Center, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507, Kyoto, Japan

    Hiroyuki Gonda & Akira Shimizu

  3. Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507, Kyoto, Japan

    Takashi Kusunoki

  4. Department of Biochemistry, Fukui Medical University, 23-3 Shimoaizuki, Matsuoka, 910-1193, Fukui, Japan

    Yoshifumi Yokota

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Correspondence to Akira Shimizu.

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Sugai, M., Gonda, H., Kusunoki, T. et al. Essential role of Id2 in negative regulation of IgE class switching. Nat Immunol 4, 25–30 (2003). https://doi.org/10.1038/ni874

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