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The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells

Nature Immunology volume 12, pages 450–459 (2011)Cite this article

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Abstract

The immunoregulatory cytokine interleukin 10 (IL-10) is expressed mainly by T helper type 2 (TH2) cells but also by TH1 cells during chronic infection. Here we observed plasticity in the expression of IL-10 and IL-13 after chronic TH1 stimulation; furthermore, the expression of Il10 and Il13 was regulated by the transcription factor E4BP4. Chronically stimulated E4BP4-deficient (Nfil3−/−; called 'E4bp4−/−' here) TH1 cells, regulatory T cells (Treg cells) and natural killer T cells (NKT cells) had attenuated expression of IL-10 and IL-13. Enforced expression of E4bp4 initiated the production of IL-10 and IL-13 by conventional TH1 cells. E4bp4−/− TH2 cells showed impairment of IL-10 production with no effect on IL-13. Our results indicate that E4BP4 has multiple functions in controlling the plasticity of IL-13 in TH1 cells and IL-10 in TH1 cells, TH2 cells, Treg cells and NKT cells.

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Figure 1: IL-13 production induced by repetitive antigen stimulation in TH1 cells.
Figure 2: E4BP4 regulates IL-13 expression in TH1 cells.
Figure 3: E4bp4 overexpression induces the expression of IL-10 and IL-13 by CD4+ T cells.
Figure 4: E4BP4 regulates the expression of Il10 and Il13 in TH1 cells.
Figure 5: Impaired production of IL-10 and IL-13 in E4bp4-deficient T cells.
Figure 6: Impaired production of IL-10 and IL-13 by CD4+ T cell subsets lacking E4BP4.
Figure 7: E4BP4 protein binds specifically to the Il13 promoter and in the Il10 locus.
Figure 8: Exacerbated colitis and EAE in E4bp4−/− mice.

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Change history

  • 09 August 2011

    In the version of this article initially published, the text on page 455 describing the results for Figure 6d was inaccurate. The corrected text should read as follows: "...however, in response to stimulation with α-GalCer, E4bp4-/- NKT cells had no detectable IL-10 expression and lower IL-13 expression, and in response to IL-25, E4bp4-/- NKT cells had lower IL-13 expression and both wild-type and E4bp4-/- NKT cells had no detectable IL-10, whereas the expression of IFN-γ and IL-4 was unaffected (Fig. 6d)." In addition, the third column of Figure 6d should include the label 'ND' above all absent bars, and the legend should define 'ND' as 'not detected'. The errors have been corrected in the HTML and PDF versions of the article.

References

  1. Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933–944 (2002).

    Article  CAS  Google Scholar 

  2. Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 8, 337–348 (2008).

    Article  CAS  Google Scholar 

  3. Iwakura, Y., Nakae, S., Saijo, S. & Ishigame, H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol. Rev. 226, 57–79 (2008).

    Article  CAS  Google Scholar 

  4. McKenzie, A.N. et al. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc. Natl. Acad. Sci. USA 90, 3735–3739 (1993).

    Article  CAS  Google Scholar 

  5. Wynn, T.A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003).

    Article  CAS  Google Scholar 

  6. Lee, G.R., Fields, P.E., Griffin, T.J. & Flavell, R.A. Regulation of the Th2 cytokine locus by a locus control region. Immunity 19, 145–153 (2003).

    Article  CAS  Google Scholar 

  7. Wilson, C.B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).

    Article  CAS  Google Scholar 

  8. Hayashi, N. et al. T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-γ and IL-13 production. Proc. Natl. Acad. Sci. USA 104, 14765–14770 (2007).

    Article  CAS  Google Scholar 

  9. Li, L., Xia, Y., Nguyen, A., Feng, L. & Lo, D. Th2-induced eotaxin expression and eosinophilia coexist with Th1 responses at the effector stage of lung inflammation. J. Immunol. 161, 3128–3135 (1998).

    CAS  PubMed  Google Scholar 

  10. Smart, J.M. & Kemp, A.S. Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease. Clin. Exp. Allergy 32, 796–802 (2002).

    Article  CAS  Google Scholar 

  11. Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

    Article  CAS  Google Scholar 

  12. Batten, M. et al. Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J. Immunol. 180, 2752–2756 (2008).

    Article  CAS  Google Scholar 

  13. Jankovic, D. et al. Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

    Article  CAS  Google Scholar 

  14. Shaw, M.H. et al. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-γ-dependent IL-10 reactivation. J. Immunol. 176, 7263–7271 (2006).

    Article  CAS  Google Scholar 

  15. Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D. CD4+CD25−Foxp3− Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007).

    Article  CAS  Google Scholar 

  16. Saraiva, M. et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209–219 (2009).

    Article  CAS  Google Scholar 

  17. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    Article  CAS  Google Scholar 

  18. Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  Google Scholar 

  19. O'Shea, J.J. & Paul, W.E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).

    Article  CAS  Google Scholar 

  20. Kishikawa, H., Sun, J., Choi, A., Miaw, S.C. & Ho, I.C. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. J. Immunol. 167, 4414–4420 (2001).

    Article  CAS  Google Scholar 

  21. Shoemaker, J., Saraiva, M. & O'Garra, A. GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J. Immunol. 176, 3470–3479 (2006).

    Article  CAS  Google Scholar 

  22. Zhu, J. et al. Conditional deletion of GATA-3 shows its essential function in TH1-TH2 responses. Nat. Immunol. 5, 1157–1165 (2004).

    Article  CAS  Google Scholar 

  23. Cowell, I.G. E4BP4/NFIL3, a PAR-related bZIP factor with many roles. Bioessays 24, 1023–1029 (2002).

    Article  CAS  Google Scholar 

  24. Zhang, W. et al. Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Mol. Cell. Biol. 15, 6055–6063 (1995).

    Article  CAS  Google Scholar 

  25. Ikushima, S. et al. Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes. Proc. Natl. Acad. Sci. USA 94, 2609–2614 (1997).

    Article  CAS  Google Scholar 

  26. Gascoyne, D.M. et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat. Immunol. 10, 1118–1124 (2009).

    Article  CAS  Google Scholar 

  27. Kamizono, S. et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206, 2977–2986 (2009).

    Article  CAS  Google Scholar 

  28. Kashiwada, M. et al. IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching. Proc. Natl. Acad. Sci. USA 107, 821–826 (2010).

    Article  CAS  Google Scholar 

  29. Lund, R., Aittokallio, T., Nevalainen, O. & Lahesmaa, R. Identification of novel genes regulated by IL-12, IL-4, or TGF-β during the early polarization of CD4+ lymphocytes. J. Immunol. 171, 5328–5336 (2003).

    Article  CAS  Google Scholar 

  30. Lund, R. et al. Identification of genes involved in the initiation of human Th1 or Th2 cell commitment. Eur. J. Immunol. 35, 3307–3319 (2005).

    Article  CAS  Google Scholar 

  31. Pai, S.Y., Truitt, M.L. & Ho, I.C. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc. Natl. Acad. Sci. USA 101, 1993–1998 (2004).

    Article  CAS  Google Scholar 

  32. Hata, H., Yoshimoto, T., Hayashi, N., Hada, T. & Nakanishi, K. IL-18 together with anti-CD3 antibody induces human Th1 cells to produce Th1- and Th2-cytokines and IL-8. Int. Immunol. 16, 1733–1739 (2004).

    Article  CAS  Google Scholar 

  33. Sugimoto, T. et al. Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J. Exp. Med. 199, 535–545 (2004).

    Article  CAS  Google Scholar 

  34. Stumhofer, J.S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

    Article  CAS  Google Scholar 

  35. McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

    Article  CAS  Google Scholar 

  36. Terashima, A. et al. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J. Exp. Med. 205, 2727–2733 (2008).

    Article  CAS  Google Scholar 

  37. Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. USA 106, 1903–1908 (2009).

    Article  CAS  Google Scholar 

  38. Koyanagi, M. et al. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J. Biol. Chem. 280, 31470–31477 (2005).

    Article  CAS  Google Scholar 

  39. Tanaka, S. et al. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells. Nat. Immunol. 12, 77–85 (2011).

    Article  CAS  Google Scholar 

  40. Roers, A. et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J. Exp. Med. 200, 1289–1297 (2004).

    Article  CAS  Google Scholar 

  41. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  CAS  Google Scholar 

  42. Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  Google Scholar 

  43. Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    Article  CAS  Google Scholar 

  44. Walter, D.M. et al. Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J. Immunol. 167, 4668–4675 (2001).

    Article  CAS  Google Scholar 

  45. Nishimura, Y. & Tanaka, T. Calcium-dependent activation of nuclear factor regulated by interleukin 3/adenovirus E4 promoter-binding protein gene expression by calcineurin/nuclear factor of activated T cells and calcium/calmodulin-dependent protein kinase signaling. J. Biol. Chem. 276, 19921–19928 (2001).

    Article  CAS  Google Scholar 

  46. Smirnov, D.V., Smirnova, M.G., Korobko, V.G. & Frolova, E.I. Tandem arrangement of human genes for interleukin-4 and interleukin-13: resemblance in their organization. Gene 155, 277–281 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. Mohrs, M. et al. Differences between IL-4- and IL-4 receptor α-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162, 7302–7308 (1999).

    CAS  PubMed  Google Scholar 

  49. Sakai, K. & Miyazaki, J. A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem. Biophys. Res. Commun. 237, 318–324 (1997).

    Article  CAS  Google Scholar 

  50. Yagi, R. et al. The IL-4 production capability of different strains of naive CD4+ T cells controls the direction of the TH cell response. Int. Immunol. 14, 1–11 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Murphy (Washington University) for DO11.10 mice on the BALB/c background; S. Akira (Osaka University) for Stat6−/− mice; F. Brombacher (University of Cape Town) for Il4r−/− mice; C. Wilson (Washington University) for Cd4-Cre mice; R. Abe (Tokyo University of Science) for the PV-1 mAb to CD28; T. Kitamura (Tokyo University) for Platinum-E packaging cells; H. Fujimoto, Y. Suzuki, K. Ikari and E. Hayashi for technical assistance; and P. Burrows for comments on the manuscript. Supported by RIKEN (Y. Motomura), the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation.

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Authors and Affiliations

  1. Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan

    Yasutaka Motomura & Masato Kubo

  2. Division of Molecular Pathology, Research Institute for Biological Science, Tokyo University of Science, Chiba, Japan

    Yasutaka Motomura & Masato Kubo

  3. Laboratory for Immunogenomics, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan

    Hiroshi Kitamura & Atsushi Hijikata

  4. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yuko Matsunaga, Koichiro Matsumoto & Hiromasa Inoue

  5. Department of Immunology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Koji Atarashi

  6. Laboratory for Immune Homeostasis, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan

    Shohei Hori

  7. Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan

    Hiroshi Watarai & Masaru Taniguchi

  8. National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Jinfang Zhu

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Contributions

Y. Motomura built the initial constructs, generated mouse lines and confirmed them in vivo, and did most of the experiments; H.K. and A.H. did microarray and bioinformatics analysis; Y. Matsunaga, K.M. and H.I. did airway hyper-responsiveness experiments; K.A. provided Il10 reporter mice; S.H. analyzed Treg cells; H.W. and M.T. analyzed NKT cells; J.Z. provided materials; and M.K. designed and coordinated experiments, supervised the project and wrote the paper.

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Correspondence to Masato Kubo.

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Motomura, Y., Kitamura, H., Hijikata, A. et al. The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat Immunol 12, 450–459 (2011). https://doi.org/10.1038/ni.2020

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