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:

The contribution of transcription factor IRF1 to the interferon-γ–interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells

Nature Immunology volume 9, pages 34–41 (2008)Cite this article

This article has been updated

Abstract

Interleukin-12 (IL-12) and interferon-γ (IFN-γ) drive T helper type 1 (TH1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-γ-induced transcription factor IRF1 was essential in TH1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor β1 subunit (IL-12Rβ1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4+ T cells. Notably, the IRF1-dependent induction of IL-12Rβ1 was essential for IFN-γ–IL-12 signaling but was dispensable for IL-23–IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rβ1, our data suggest that distinct thresholds of IL-12Rβ1 expression are required for TH1 versus TH-17 differentiation.

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: IRF1 in the TH1 differentiation of naive CD4+ T cells.
Figure 2: Impaired IL-12 signaling due to the defective expression of IL-12Rβ1 in Irf1−/− CD4+ T cells.
Figure 3: Differential regulation of IL-12 responsiveness and IFN-γ production by IRF1 and T-bet.
Figure 4: IRF1-mediated control of Il12rb1 transcription.
Figure 5: Retroviral expression of IL-12Rβ1 restores IFN-γ production in Irf1−/− CD4+ T cells.
Figure 6: Differential regulation of IL-12Rβ1 expression in TH1 and TH-17 cells.
Figure 7: Impaired TH1 immune responses of Irf1−/− CD4+ T cells.

Similar content being viewed by others

Change history

  • 13 December 2007

    In the version of this supplementary file originally posted online, a band in the middle panel of Fig. 4C was not visible; the contrast has been adjusted appropriately. The error has been corrected in the PDF version of the article.

References

  1. Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    Article  CAS  Google Scholar 

  2. Glimcher, L.H. & Murphy, K.M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14, 1693–1711 (2000).

    CAS  PubMed  Google Scholar 

  3. Murphy, K.M. et al. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18, 451–494 (2000).

    Article  CAS  Google Scholar 

  4. Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  5. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    Article  CAS  Google Scholar 

  6. Weaver, C.T., Hatton, R.D., Mangan, P.R. & Harrington, L.E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).

    Article  CAS  Google Scholar 

  7. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  Google Scholar 

  8. Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

    Article  CAS  Google Scholar 

  9. Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    Article  CAS  Google Scholar 

  10. Szabo, S.J., Sullivan, B.M., Peng, S.L. & Glimcher, L.H. Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).

    Article  CAS  Google Scholar 

  11. 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 

  12. 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 

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

    Article  CAS  Google Scholar 

  14. Mullen, A.C. et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907–1910 (2001).

    Article  CAS  Google Scholar 

  15. Murphy, K.M. 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 

  16. Szabo, S.J., Dighe, A.S., Gubler, U. & Murphy, K.M. Regulation of the interleukin (IL)-12Rβ2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J. Exp. Med. 185, 817–824 (1997).

    Article  CAS  Google Scholar 

  17. Mullen, A.C. et al. Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction. Nat. Immunol. 3, 652–658 (2002).

    Article  CAS  Google Scholar 

  18. Usui, T., Nishikomori, R., Kitani, A. & Strober, W. GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rβ2 chain or T-bet. Immunity 18, 415–428 (2003).

    Article  CAS  Google Scholar 

  19. Usui, T. et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 203, 755–766 (2006).

    Article  CAS  Google Scholar 

  20. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  Google Scholar 

  21. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    Article  CAS  Google Scholar 

  22. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).

    Article  CAS  Google Scholar 

  23. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).

    Article  CAS  Google Scholar 

  24. Taki, S. et al. Multistage regulation of Th1-type immune responses by the transcription factor IRF-1. Immunity 6, 673–679 (1997).

    Article  CAS  Google Scholar 

  25. Lohoff, M. et al. Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity 6, 681–689 (1997).

    Article  CAS  Google Scholar 

  26. Liu, J., Cao, S., Herman, L.M. & Ma, X. Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-γ-primed IL-12 production by IFN regulatory factor 1. J. Exp. Med. 198, 1265–1276 (2003).

    Article  CAS  Google Scholar 

  27. Maruyama, S. et al. Identification of IFN regulatory factor-1 binding site in IL-12 p40 gene promoter. J. Immunol. 170, 997–1001 (2003).

    Article  CAS  Google Scholar 

  28. McElligott, D.L. et al. CD4+ T cells from IRF-1-deficient mice exhibit altered patterns of cytokine expression and cell subset homeostasis. J. Immunol. 159, 4180–4186 (1997).

    CAS  PubMed  Google Scholar 

  29. Elser, B. et al. IFN-γ represses IL-4 expression via IRF-1 and IRF-2. Immunity 17, 703–712 (2002).

    Article  CAS  Google Scholar 

  30. Hwang, E.S., Szabo, S.J., Schwartzberg, P.L. & Glimcher, L.H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307, 430–433 (2005).

    Article  CAS  Google Scholar 

  31. Yamane, H., Igarashi, O., Kato, T. & Nariuchi, H. Positive and negative regulation of IL-12 receptor expression of naive CD4+ T cells by CD28/CD152 co-stimulation. Eur. J. Immunol. 30, 3171–3180 (2000).

    Article  CAS  Google Scholar 

  32. Szabo, S.J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002).

    Article  CAS  Google Scholar 

  33. Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).

    Article  CAS  Google Scholar 

  34. Mangan, P.R. et al. Transforming growth factor-beta induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  Google Scholar 

  35. Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).

    Article  CAS  Google Scholar 

  36. Wenner, C.A., Guler, M.L., Macatonia, S.E., O'Garra, A. & Murphy, K.M. Roles of IFN-γ and IFN-α in IL-12-induced T helper cell-1 development. J. Immunol. 156, 1442–1447 (1996).

    CAS  PubMed  Google Scholar 

  37. Musikacharoen, T. et al. Interleukin-15 induces IL-12 receptor β1 gene expression through PU.1 and IRF 3 by targeting chromatin remodeling. Blood 105, 711–720 (2005).

    Article  CAS  Google Scholar 

  38. Zhang, F. & Boothby, M. T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent. J. Exp. Med. 203, 1493–1505 (2006).

    Article  CAS  Google Scholar 

  39. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat. Immunol. 3, 643–651 (2002).

    Article  CAS  Google Scholar 

  40. te Velde, A.A. et al. Comparative analysis of colonic gene expression of three experimental colitis models mimicking inflammatory bowel disease. Inflamm. Bowel Dis. 13, 325–330 (2007).

    Article  Google Scholar 

  41. Silverberg, M.S. et al. Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease. Eur. J. Hum. Genet. 15, 328–335 (2007).

    Article  CAS  Google Scholar 

  42. Clavell, M. et al. Detection of interferon regulatory factor-1 in lamina propria mononuclear cells in Crohn's disease. J. Pediatr. Gastroenterol. Nutr. 30, 43–47 (2000).

    Article  CAS  Google Scholar 

  43. Matsuyama, T. et al. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell 75, 83–97 (1993).

    Article  CAS  Google Scholar 

  44. 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 

  45. Huang, S. et al. Immune response in mice that lack the interferon-γ receptor. Science 259, 1742–1745 (1993).

    Article  CAS  Google Scholar 

  46. Wu, C., Ferrante, J., Gately, M.K. & Magram, J. Characterization of IL-12 receptor β1 chain (IL-12Rβ1)-deficient mice: IL-12Rβ1 is an essential component of the functional mouse IL-12 receptor. J. Immunol. 159, 1658–1665 (1997).

    CAS  PubMed  Google Scholar 

  47. Honda, K. et al. Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc. Natl. Acad. Sci. USA 100, 10872–10877 (2003).

    Article  CAS  Google Scholar 

  48. Ouyang, W. et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9, 745–755 (1998).

    Article  CAS  Google Scholar 

  49. Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889–901 (2002).

    Article  CAS  Google Scholar 

  50. Martin-Fontecha, A. et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5, 1260–1265 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Flavell, R. Medzhitov, M. Feldmann, A. Rao and G. Nunez for discussions; L. Glimcher (Harvard School of Public Health) for the T-bet retrovirus vector and Tbx21−/− mice; R. Kastelein (DNAX Research Institute) for the IL-12Rβ1 bicistronic retrovirus vector; S. Hida and S. Taki (Shinshu University Graduate School of Medicine) for Rag1−/− mice; K. Ogasawara, A. Takaoka, H. Takayanagi, Y. Ohba, T. Tamura, H. Yanai, H. Katoh, C. Nakajima, K. Tsushima and H. Negishi for advice; Y. Matsuno and M. Shishido for technical assistance; D. Savitsky for critically reading the manuscript; and T. Yokochi and A. Sawa for encouragement. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant for Advanced Research on Cancer and a Grant-In-Aid for Scientific Research on Priority Areas), the Ishidu Shun Memorial Foundation (S.K.) and the Japan Society for the Promotion of Science (S.V.).

Author information

Authors and Affiliations

  1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan

    Shin-ichi Kano, Kojiro Sato, Sabine Vollstedt, Sunhwa Kim, Kenya Honda & Tadatsugu Taniguchi

  2. Department of Pathology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan

    Yasuyuki Morishita

  3. Department of Surgery and the Graduate Program in Immunology, Section of General Surgery, University of Michigan School of Medicine, University of Michigan Medical Center, Ann Arbor, 48109, Michigan, USA

    Keith Bishop

  4. Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Masato Kubo

Authors
  1. Shin-ichi Kano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kojiro Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuyuki Morishita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabine Vollstedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sunhwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keith Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenya Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masato Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tadatsugu Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.-i.K. designed and did the experiments, analyzed the data and wrote the paper; K.S. provided some of the initial results and ideas; Y.M. did the histological analysis of colitis; S.V. and S.K. did some of the experiments and analyzed the data; K.B., K.H. and M.K. generated key materials and analyzed some of the critical data; and T.T. supervised all the work and wrote the paper.

Corresponding author

Correspondence to Tadatsugu Taniguchi.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Table 1 and Methods (PDF 2072 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kano, Si., Sato, K., Morishita, Y. et al. The contribution of transcription factor IRF1 to the interferon-γ–interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells. Nat Immunol 9, 34–41 (2008). https://doi.org/10.1038/ni1538

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1538

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