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:

Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells

Nature Immunology volume 13, pages 481–490 (2012)Cite this article

Subjects

Abstract

The maintenance of immune homeostasis requires regulatory T cells (Treg cells). Here we found that Treg cell–specific ablation of Ubc13, a Lys63 (K63)-specific ubiquitin-conjugating enzyme, caused aberrant T cell activation and autoimmunity. Although Ubc13 deficiency did not affect the survival of Treg cells or expression of the transcription factor Foxp3, it impaired the in vivo suppressive function of Treg cells and rendered them sensitive to the acquisition of T helper type 1 (TH1) cell– and interleukin 17 (IL-17)-producing helper T (TH17) cell–like effector phenotypes. This function of Ubc13 involved its downstream target, the kinase IKK. The Ubc13-IKK signaling axis controlled the expression of specific Treg cell effector molecules, including IL-10 and SOCS1. Collectively, our findings suggest that the Ubc13-IKK signaling axis regulates the molecular program that maintains Treg cell function and prevents Treg cells from acquiring inflammatory phenotypes.

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: Treg cell–specific ablation of Ubc13 causes systemic autoimmunity.
Figure 2: Treg cell–specific ablation of Ubc13 impairs T-cell homeostasis.
Figure 3: Ubc13 is dispensable for the homeostasis and in vitro suppressive activity of Treg cells.
Figure 4: Treg cell–specific ablation of Ubc13 impairs the in vivo immunosuppressive function of Treg cells.
Figure 5: Ubc13-deficient Treg cells are sensitive to lymphopenic and inflammatory conditions for the acquisition of effector functions.
Figure 6: The Treg cell–specific function of Ubc13 involves its downstream target, IKK.
Figure 7: Ubc13 is dispensable for the expression of Treg cell signature genes but regulates the expression Socs1 and Il10.
Figure 8: Synergistic activation of the Socs1 promoter by IKK2 and STAT3 via a STAT–NF-κB composite site.
Figure 9: A SOCS1 mimetic peptide partially 'rescues' the functional defect of Ubc13-deficient Treg cells both in vitro and in vivo.

Similar content being viewed by others

References

  1. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Rudensky, A.Y. Regulatory T cells and Foxp3. Immunol. Rev. 241, 260–268 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shevach, E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Rubtsov, Y.P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bailey-Bucktrout, S.L. & Bluestone, J.A. Regulatory T cells: stability revisited. Trends Immunol. 32, 301–306 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hori, S. Regulatory T cell plasticity: beyond the controversies. Trends Immunol. 32, 295–300 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Duarte, J.H., Zelenay, S., Bergman, M.L., Martins, A.C. & Demengeot, J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur. J. Immunol. 39, 948–955 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ayyoub, M. et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt. Proc. Natl. Acad. Sci. USA 106, 8635–8640 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Voo, K.S. et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc. Natl. Acad. Sci. USA 106, 4793–4798 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Takahashi, R. et al. SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production. J. Exp. Med. 208, 2055–2067 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu, L., Kitani, A., Fuss, I. & Strober, W. Cutting edge: regulatory T cells induce CD4+CD25−Foxp3− T cells or are self-induced to become TH17 cells in the absence of exogenous TGF-β. J. Immunol. 178, 6725–6729 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Collins, E.L. et al. Inhibition of SOCS1−/− lethal autoinflammatory disease correlated to enhanced peripheral Foxp3+ regulatory T cell homeostasis. J. Immunol. 187, 2666–2676 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Bhoj, V.G. & Chen, Z.J. Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Sun, L., Deng, L., Ea, C.-K., Xia, Z.-P. & Chen, Z.J. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14, 289–301 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Yamamoto, M. et al. Cutting edge: pivotal function of Ubc13 in thymocyte TCR signaling. J. Immunol. 177, 7520–7524 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Isomura, I. et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J. Exp. Med. 206, 3001–3014 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Long, M., Park, S.G., Strickland, I., Hayden, M.S. & Ghosh, S. Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921–931 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamamoto, M. et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat. Immunol. 7, 962–970 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Zhou, X. et al. Selective miRNA disruption in Treg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 1983–1991 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Morrissey, P.J., Charrier, K., Braddy, S., Liggitt, D. & Watson, J.D. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J. Exp. Med. 178, 237–244 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Mattioli, I. et al. Transient and selective NF-κB p65 serine 536 phosphorylation induced by T cell costimulation is mediated by IκB kinase β and controls the kinetics of p65 nuclear import. J. Immunol. 172, 6336–6344 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Sasaki, Y. et al. Canonical NF-κB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 24, 729–739 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of TH17 cell-mediated inflammation. Immunity 34, 566–578 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huber, S. et al. TH17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34, 554–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pillemer, B.B., Xu, H., Oriss, T.B., Qi, Z. & Ray, A. Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur. J. Immunol. 37, 2082–2089 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Cao, S., Zhang, X., Edwards, J.P. & Mosser, D.M. NF-κB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. J. Biol. Chem. 281, 26041–26050 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Benkhart, E.M., Siedlar, M., Wedel, A., Werner, T. & Ziegler-Heitbrock, H.W. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J. Immunol. 165, 1612–1617 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Saito, H. et al. IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-γ. J. Immunol. 164, 5833–5843 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Diehl, S. et al. Inhibition of TH1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805–815 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Charoenthongtrakul, S., Zhou, Q., Shembade, N., Harhaj, N.S. & Harhaj, E.W. Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-κB-dependent induction of SOCS1. J. Virol. 85, 6955–6962 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Flowers, L.O. et al. Characterization of a peptide inhibitor of Janus kinase 2 that mimics suppressor of cytokine signaling 1 function. J. Immunol. 172, 7510–7518 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Flowers, L.O., Subramaniam, P.S. & Johnson, H.M.A. SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells. Oncogene 24, 2114–2120 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Jager, L.D. et al. The kinase inhibitory region of SOCS-1 is sufficient to inhibit T-helper 17 and other immune functions in experimental allergic encephalomyelitis. J. Neuroimmunol. 232, 108–118 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Kryczek, I. et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J. Immunol. 186, 4388–4395 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Chang, M. et al. The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat. Immunol. 12, 1002–1009 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Harhaj, E.W., Maggirwar, S.B. & Sun, S.-C. Inhibition of p105 processing by NF-κB proteins in transiently transfected cells. Oncogene 12, 2385–2392 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Karin (University of California, San Diego) for the IKK2(CA) expression vector; T. Kishimoto (Osaka University) for the mouse Socs1-luc reporter; and personnel from the flow cytometry, DNA analysis, and histology core facilities at MD Anderson Cancer Center for technical assistance. This work is supported by the US National Institutes of Health (AI057555, AI064639 and GM84459) and the G.S. Hogan Gastrointestinal Cancer Research Fund.

Author information

Author notes

  1. Xuefeng Wu

    Present address: Present address: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, California, USA.,

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Jae-Hoon Chang, Yichuan Xiao, Hongbo Hu, Jin Jin, Jiayi Yu, Xiaofei Zhou, Xuefeng Wu, Xuhong Cheng & Shao-Cong Sun

  2. Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida, USA

    Howard M Johnson

  3. Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Shizuo Akira

  4. Institute for Genetics, Center for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

    Manolis Pasparakis

  5. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA

    Shao-Cong Sun

Authors
  1. Jae-Hoon Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yichuan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongbo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiayi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaofei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuefeng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Howard M Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shizuo Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Manolis Pasparakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xuhong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shao-Cong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.-H.C. designed and did the research, prepared the figures, and wrote part of the manuscript; Y.X. did the luciferase assays; X.Z. provided technical help for adoptive transfer; H.H. did the Ubc13 immunoblot analysis; J.J. constructed the mutant Socs1 luciferase plasmid; J.Y., X.C. and X.W. contributed to the generation of mouse models; H.M.J., S.A. and M.P. contributed reagents; and S.-C.S. designed the research and wrote the manuscript.

Corresponding author

Correspondence to Shao-Cong Sun.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Table 1 (PDF 19955 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chang, JH., Xiao, Y., Hu, H. et al. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 13, 481–490 (2012). https://doi.org/10.1038/ni.2267

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2267

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