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Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3

Nature Immunology volume 12, pages 86–95 (2011)Cite this article

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Abstract

The molecular mechanisms that direct transcription of the gene encoding the transcription factor Foxp3 in CD4+ T cells remain ill-defined. We show here that deletion of the DNA-binding inhibitor Id3 resulted in the defective generation of Foxp3+ regulatory T cells (Treg cells). We identify two transforming growth factor-β1 (TGF-β1)-dependent mechanisms that were vital for activation of Foxp3 transcription and were defective in Id3−/− CD4+ T cells. Enhanced binding of the transcription factor E2A to the Foxp3 promoter promoted Foxp3 transcription. Id3 was required for relief of inhibition by the transcription factor GATA-3 at the Foxp3 promoter. Furthermore, Id3−/− T cells showed greater differentiation into the TH17 subset of helper T cells in vitro and in a mouse asthma model. Therefore, a network of factors acts in a TGF-β-dependent manner to control Foxp3 expression and inhibit the development of TH17 cells.

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Figure 1: Id3 regulates the generation of Foxp3+ Treg cells.
Figure 2: Id3−/− T cells fails to generate Foxp3+ Treg cells in response to TGF-β1.
Figure 3: Enrichment of E2A at the Foxp3 promoter.
Figure 4: Binding of E2A to the Foxp3 promoter is required for activation of Foxp3 by TGF-β1.
Figure 5: Id3 deficiency increases GATA-3.
Figure 6: Id3−/− CD4+ T cells differentiate into TH17 cells in response to TGF-β1 in vitro.
Figure 7: Id3 regulates TH17 cells in HDM-induced asthma.

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References

  1. Bluestone, J.A. & Abbas, A.K. Natural versus adaptive regulatory T cells. Nat. Rev. Immunol. 3, 253–257 (2003).

    Article  CAS  Google Scholar 

  2. Fontenot, J.D. & Rudensky, A.Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6, 331–337 (2005).

    Article  CAS  Google Scholar 

  3. Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000).

    Article  CAS  Google Scholar 

  4. Shevach, E.M. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

    Article  CAS  Google Scholar 

  5. von Boehmer, H. Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6, 338–344 (2005).

    Article  CAS  Google Scholar 

  6. Waldmann, H., Adams, E., Fairchild, P. & Cobbold, S. Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol. Rev. 212, 301–313 (2006).

    Article  CAS  Google Scholar 

  7. Hill, J.A., Benoist, C. & Mathis, D. Treg cells: guardians for life. Nat. Immunol. 8, 124–125 (2007).

    Article  CAS  Google Scholar 

  8. Belkaid, Y. & Tarbell, K. Regulatory T cells in the control of host-microorganism interactions. Annu. Rev. Immunol. 27, 551–589 (2009).

    Article  CAS  Google Scholar 

  9. Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  Google Scholar 

  10. Curotto de Lafaille, M.A. & Lafaille, J.J. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30, 626–635 (2009).

    CAS  PubMed  Google Scholar 

  11. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).

    Article  CAS  Google Scholar 

  12. Liu, Y. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632–640 (2008).

    Article  CAS  Google Scholar 

  13. Wan, Y.Y. & Flavell, R.A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl. Acad. Sci. USA 102, 5126–5131 (2005).

    Article  CAS  Google Scholar 

  14. Nolting, J. et al. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J. Exp. Med. 206, 2131–2139 (2009).

    Article  CAS  Google Scholar 

  15. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202 (2008).

    Article  CAS  Google Scholar 

  16. Yang, X.O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).

    Article  CAS  Google Scholar 

  17. Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  Google Scholar 

  18. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  Google Scholar 

  19. Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. 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 

  22. Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).

    Article  CAS  Google Scholar 

  23. 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 

  24. Murre, C. Helix-loop-helix proteins and lymphocyte development. Nat. Immunol. 6, 1079–1086 (2005).

    Article  CAS  Google Scholar 

  25. Rivera, R.R., Johns, C.P., Quan, J., Johnson, R.S. & Murre, C. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. Immunity 12, 17–26 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Li, H., Dai, M. & Zhuang, Y.A. T cell intrinsic role of Id3 in a mouse model for primary Sjogren's syndrome. Immunity 21, 551–560 (2004).

    Article  CAS  Google Scholar 

  28. Thornton, A.M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).

    Article  CAS  Google Scholar 

  29. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  Google Scholar 

  30. Nakao, A. et al. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389, 631–635 (1997).

    Article  CAS  Google Scholar 

  31. Cohen-Kaminsky, S. et al. Chromatin immunoselection defines a TAL-1 target gene. EMBO J. 17, 5151–5160 (1998).

    Article  CAS  Google Scholar 

  32. Ghosh, I., Bishop, P. & Chmielewski, J. DNA binding properties of basic helix-loop-helix fusion proteins of Tal and E47. J. Pept. Res. 57, 354–360 (2001).

    Article  CAS  Google Scholar 

  33. Ikawa, T., Kawamoto, H., Goldrath, A.W. & Murre, C. E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment. J. Exp. Med. 203, 1329–1342 (2006).

    Article  CAS  Google Scholar 

  34. Sun, X.H. & Baltimore, D. An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers. Cell 64, 459–470 (1991).

    Article  CAS  Google Scholar 

  35. Ruan, Q. et al. Development of Foxp3+ regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31, 932–940 (2009).

    Article  CAS  Google Scholar 

  36. Jones, M.E., Kondo, M. & Zhuang, Y. A tamoxifen inducible knock-in allele for investigation of E2A function. BMC Dev. Biol. 9, 51 (2009).

    Article  Google Scholar 

  37. Wojciechowski, J., Lai, A., Kondo, M. & Zhuang, Y. E2A and HEB are required to block thymocyte proliferation prior to pre-TCR expression. J. Immunol. 178, 5717–5726 (2007).

    Article  CAS  Google Scholar 

  38. 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 

  39. Mantel, P.Y. et al. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol. 5, e329 (2007).

    Article  Google Scholar 

  40. Gorelik, L., Fields, P.E. & Flavell, R.A. Cutting edge: TGF-β inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165, 4773–4777 (2000).

    Article  CAS  Google Scholar 

  41. Zhu, J. & Paul, W.E. CD4 T cells: fates, functions, and faults. Blood 112, 1557–1569 (2008).

    Article  CAS  Google Scholar 

  42. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    Article  CAS  Google Scholar 

  43. Xi, H., Schwartz, R., Engel, I., Murre, C. & Kersh, G.J. Interplay between RORγt, Egr3, and E proteins controls proliferation in response to pre-TCR signals. Immunity 24, 813–826 (2006).

    Article  CAS  Google Scholar 

  44. Schnyder-Candrian, S. et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).

    Article  CAS  Google Scholar 

  45. Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

    Article  CAS  Google Scholar 

  46. Rudra, D. et al. Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 10, 1170–1177 (2009).

    Article  CAS  Google Scholar 

  47. Kim, H.P. & Leonard, W.J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543–1551 (2007).

    Article  CAS  Google Scholar 

  48. Perruche, S. et al. Lethal effect of CD3-specific antibody in mice deficient in TGF-β1 by uncontrolled flu-like syndrome. J. Immunol. 183, 953–961 (2009).

    Article  CAS  Google Scholar 

  49. Perruche, S. et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells. Nat. Med. 14, 528–535 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y.H. Chen, Q. Ruan and M. Tone (University of Pennsylvania) for Foxp3 constructs and EL4 LAF cells. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (US National Institutes of Health).

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Author notes

  1. Takashi Maruyama and Jun Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institutes of Health, Bethesda, Maryland, USA

    Takashi Maruyama, Jun Li, Joanne E Konkel, Pin Zhang, Brian F Zamarron & WanJun Chen

  2. Oral Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    Jose P Vaque & J Silvio Gutkind

  3. Department of Microbiology and Molecular Biology, George Mason University, Manassas, Virginia, USA

    Weifeng Wang, Dongyang Yu & Yuntao Wu

  4. Department of Immunology, Duke University, Durham, North Carolina, USA

    Baojun Zhang & Yuan Zhuang

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  1. Takashi Maruyama
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Contributions

T.M. and J.L. designed and did experiments, analyzed data and contributed to the writing of the manuscript; J.P.V. designed and did ChIP experiments, analyzed data and contributed to the writing of the manuscript; J.E.K. did experiments, analyzed data and contributed to the writing of the manuscript; Y.W. designed and W.W. and D.Y. did the luciferase, E2A-knockdown and Id3 immunoblot experiments and analyzed data; B.Z. and Y.Z. generated and identified mice doubly deficient in E2A and HEB and provided critical input; P.Z. and B.F.Z. did experiments; J.S.G. supervised and designed the ChIP study and contributed to the writing of the manuscript; and W.C. conceived of the research, directed the study, designed experiments, analyzed data and wrote the manuscript.

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Correspondence to WanJun Chen.

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Maruyama, T., Li, J., Vaque, J. et al. Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3. Nat Immunol 12, 86–95 (2011). https://doi.org/10.1038/ni.1965

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