Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells

Nature Immunology volume 4, pages 687–693 (2003)Cite this article

This article has been updated

Abstract

CpG DNA has immunomodulatory effects, such as the suppression of allergic responses mediated by type II T cell help (TH2). Here we report that CpG, but not lipopolysaccharide (LPS), rapidly induces expression of T-bet mRNA in purified B cells. Up-regulation of T-bet by CpG is abrogated in mice deficient in Toll-like receptor 9 (TLR9) and MyD88, but remains intact in B cells deficient in STAT1 (signal transducer and activator of transcription 1). Interleukin 12 (IL-12) alone does not up-regulate T-bet mRNA, but greatly enhances CpG-induced T-bet expression. Furthermore, CpG inhibits immunoglobulin G1 (IgG1) and IgE switching induced by IL-4 and CD40 signaling in purified B cells, and this effect correlates with up-regulation of T-bet. Thus, CpG triggers anti-allergic immune responses by directly regulating T-bet expression via a signaling pathway in B cells that is dependent upon TLR9, independent of interferon-γ (IFN-γ)-STAT1 and synergistic with IL-12.

*Note: In the version of this article initially published online, some of the nomenclature was incorrect. This has been corrected for the HTML and print versions of the article.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Induction of T-bet in mouse splenocytes.
Figure 2: Stimulus-induced STAT1α/β phosphorylation in splenocytes.
Figure 3: T-bet transactivation and STAT1 phosphorylation in MyD88- or TLR9-deficient mice.
Figure 4: Cell types expressing T-bet in response to CpG.
Figure 5: CpG-induced, IFN-γ–STAT1-independent expression of T-bet in purified B cells.
Figure 6: Characterization of signal cascades involved in CpG-induced T-bet transactivation in purified B cells.
Figure 7: Inhibition of IL-4– and CD40-ligation–induced IgG1, IgG2a and IgE production.

Similar content being viewed by others

Change history

  • 15 June 2003

    appended aop PDF with erratum (will be corrected for print issue), and placed footnote in SGML at abstract

References

  1. Modlin, R.L. Mammalian toll-like receptors. Ann. Allergy Asthma Immunol. 88, 543–547 (2002).

    Article  CAS  Google Scholar 

  2. Yang, D., Biragyn, A., Kwak, L.W. & Oppenheim, J.J. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 23, 291–296 (2002).

    Article  CAS  Google Scholar 

  3. Asnagli, H. & Murphy, M.K. Stability and commitment in T helper cell development. Curr. Opin. Immuno. 13, 242–247 (2001).

    Article  CAS  Google Scholar 

  4. 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 

  5. Takeda, K. et al. Essential role of Stat6 in IL-4 signalling. Nature 380, 627–630 (1996).

    Article  CAS  Google Scholar 

  6. Murphy, KM. et al. T helper differentiation proceeds through Stat1-dependent, Stat4-dependent and Stat4-independent phases. Curr. Top. Microbiol. Immunol. 238, 13–26 (1999).

    CAS  PubMed  Google Scholar 

  7. Tokunaga, T. et al. Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J. Nat. Cancer Inst. 72, 955–962 (1984).

    CAS  PubMed  Google Scholar 

  8. Tokunaga, T., Yamamoto, S. & Namba, K. A synthetic single-stranded DNA, poly(dG, dC), induces interferon-α/β and -γ, augments tumor growth. Jpn. J. Cancer Res. 79, 682–686 (1998).

    Article  Google Scholar 

  9. Stacey, K.J., Sweet, M.J. & Hume, D.A. Macrophages ingest and are activated by bacterial DNA. J. Immunol. 157, 2116–2122 (1996).

    CAS  PubMed  Google Scholar 

  10. Halpern, M.D., Kurlander, R.J. & Pisetsky, D.S. Bacterial DNA induces murine interferon-_ production by stimulation of interleukin-12 and tumor necrosis factor-α. Cell Immunol. 167, 72–78 (1996).

    Article  CAS  Google Scholar 

  11. Roman, M. et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat. Med. 3, 849–854 (1997).

    Article  CAS  Google Scholar 

  12. Ballas, Z.K., Rasmussen, W.L. & Krieg, A.M. Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J. Immunol. 157, 1840–1845 (1996).

    CAS  PubMed  Google Scholar 

  13. Krieg, A.M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).

    Article  CAS  Google Scholar 

  14. Klinman, D.M., Yi, A.K., Beaucage, S.L., Conover, J. & Krieg, A.M. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon γ. Proc. Natl. Acad. Sci. USA 93, 2879–2883 (1996).

    Article  CAS  Google Scholar 

  15. Yi, A.K., Chace, J.H., Cowdery, J.S. & Krieg, A.M. IFN-γ promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligodeoxynucleotides. J. Immunol. 156, 558–564 (1996).

    CAS  PubMed  Google Scholar 

  16. Bohle, B. et al. Oligodeoxynucleotides containing CpG motifs induce IL-12, IL-18 and IFN-γ production in cells from allergic individuals and inhibit IgE synthesis in vitro. Eur. J. Immunol. 29, 2344–2353 (1999).

    Article  CAS  Google Scholar 

  17. Parronchi, P. et al. Phosphorothioate oligodeoxynucleotides promote the in vitro development of human allergen-specific CD4+ T cells into Th1 effectors. J. Immunol. 163, 5946–5953 (1999).

    CAS  PubMed  Google Scholar 

  18. Fujieda, S. et al. Synthetic oligodeoxynucleotides inhibit IgE induction in human lymphocytes. Am. J. Respir. Crit. Care Med. 162, 232–239 (2000).

    Article  CAS  Google Scholar 

  19. Kline, J.N. et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol. 160, 2555–2559 (1998).

    CAS  PubMed  Google Scholar 

  20. Sur, S. et al. Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides. J. Immunol. 162, 6284–6293 (1999).

    CAS  PubMed  Google Scholar 

  21. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

    Article  CAS  Google Scholar 

  22. Kaisho, T. & Akira, S. Toll-like receptors as adjuvant receptors. Biochim. Biophys. Acta 1589, 1–13 (2002).

    Article  CAS  Google Scholar 

  23. Lighvani, A.A. et al. T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells. Proc. Natl. Acad. Sci. USA 98, 15137–15142 (2001).

    Article  CAS  Google Scholar 

  24. Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nat. Immunol. 3, 392–398 (2002).

    Article  CAS  Google Scholar 

  25. Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat. Immunol. 3, 549–557 (2002).

    Article  CAS  Google Scholar 

  26. Hartmann, G. & Krieg, A.M. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J. Immunol. 164, 944–953 (2000).

    Article  CAS  Google Scholar 

  27. Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O. & Akira, S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14, 1225–1231 (2002).

    Article  CAS  Google Scholar 

  28. Hacker, H. et al. Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells. EMBO J. 18, 6973–6982 (1999).

    Article  CAS  Google Scholar 

  29. Choudhury, B.K. et al. In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J. Immunol. 169, 5955–5961 (2002).

    Article  CAS  Google Scholar 

  30. Peng, S.L., Szabo, S.J. & Glimcher, L.H. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc. Natl. Acad. Sci. USA 99, 5545–5550 (2002).

    Article  CAS  Google Scholar 

  31. Szabo, S.J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  32. Decker, T., Stockinger, S., Karaghiosoff, M., Muller, M. & Kovarik, P. IFNs and STATs in innate immunity to microorganisms. J. Clin. Invest. 109, 1271–1277 (2002).

    Article  CAS  Google Scholar 

  33. Chimushi, T. et al. CpG inhibits TH2-dependent airway inflammation at effector phase. (abstract in Japanese) Proc. Jap. Soc. Immunol. 32, 238 (2002).

    Google Scholar 

  34. Rothman, P., Lutzker, S., Cook, W., Coffman, R. & Alt, F.W. Mitogen plus interleukin-4 induction of C epsilon transcripts in B lymphoid cells. J. Exp. Med. 168, 2385–2389 (1988).

    Article  CAS  Google Scholar 

  35. Verthelyi, D. et al. Human peripheral blood cells differentially recognize and respond to two distinct CpG motifs. J. Immunol. 166, 2372–2377 (2001).

    Article  CAS  Google Scholar 

  36. Wild, J.S. & Sur, S. CpG oligonucleotide modulation of allergic inflammation. Allergy 56, 365–376 (2001).

    Article  CAS  Google Scholar 

  37. Bohle, B., Orel, L., Kraft, D. & Ebner, C. Oligodeoxynucleotides containing CpG motifs induce low levels of TNF-α in human B lymphocytes: possible adjuvants for Th1 responses. J. Immunol. 166, 3743–3756 (2001).

    Article  CAS  Google Scholar 

  38. Meraz, M.A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442 (1996).

    Article  CAS  Google Scholar 

  39. Magram, J. et al. IL-12-deficient mice are defective in IFN-γ production and type I cytokine responses. Immunity 4, 471–481 (1996).

    Article  CAS  Google Scholar 

  40. Linehan, L.A., Warren, W.D., Thompson, P.A., Grusby, M.J. & Berton, M.T. STAT6 is required for IL-4-induced germline Ig gene transcription and switch recombination. J. Immunol. 161, 302–310 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. Nakashima and Y. Manabe for experimental assistance and J. Encinas for valuable discussions.

Author information

Authors and Affiliations

  1. Research Center Kyoto, Bayer Yakuhin Ltd., 6-5-1-3 Kunimidai, Kizu-cho, Soraku-gun, 619-0216, Kyoto, Japan

    Ningshu Liu, Noriko Ohnishi, Lin Ni & Kevin B Bacon

  2. Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Shizuo Akira

Authors
  1. Ningshu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noriko Ohnishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shizuo Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin B Bacon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ningshu Liu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, N., Ohnishi, N., Ni, L. et al. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. Nat Immunol 4, 687–693 (2003). https://doi.org/10.1038/ni941

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni941

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing