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 histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance

An Erratum to this article was published on 01 June 2009

This article has been updated

Abstract

Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical 'decision' is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical 'decision' with substantial implications in autoimmunity, transplantation and cancer immunotherapy.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Overexpression of HDAC11 abrogates the expression of IL-10 mRNA in LPS-treated macrophages.
Figure 2: Expression of IL-10 and IL-12 mRNA in APCs overexpressing or lacking HDAC11.
Figure 3: The distal region of the Il10 promoter is required for HDAC11-mediated gene repression.
Figure 4: Chromatin modifications induced by HDAC11 overexpression.
Figure 5: Chromatin modification in APCs lacking HDAC11.
Figure 6: Phenotypic and functional analysis of PEMs overexpressing or lacking HDAC11.
Figure 7: CD4+ T cell responses to cognate antigen presented by PEMs overexpressing or lacking HDAC11.

Similar content being viewed by others

Change history

  • 18 May 2009

    NOTE: In the original version of the article published, the units for IL-12 in Fig. 6b are incorrect. The correct units should be ‘(ng/ml)’. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C. & Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 20, 621–667 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Kurts, C., Kosaka, H., Carbone, F.R., Miller, J.F. & Heath, W.R. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8+ T cells. J. Exp. Med. 186, 239–245 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Adler, A.J. et al. CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells. J. Exp. Med. 187, 1555–1564 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Huang, F.P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–444 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Munn, D.H. et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Scheinecker, C., McHugh, R., Shevach, E.M. & Germain, R.N. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J. Exp. Med. 196, 1079–1090 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Belz, G.T. et al. The CD8α+ dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J. Exp. Med. 196, 1099–1104 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rabinovich, G.A., Gabrilovich, D. & Sotomayor, E.M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. & Lanzavecchia, A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1–polarizing program in dendritic cells. Nat. Immunol. 6, 769–776 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Li, M.O. & Flavell, R.A. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity 28, 468–476 (2008).

    Article  PubMed  Google Scholar 

  15. 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 

  16. Foster, S.L., Hargreaves, D.C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, X., Edwards, J.P. & Mosser, D.M. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J. Immunol. 177, 1282–1288 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Yao, Y., Li, W., Kaplan, M.H. & Chang, C.H. Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by dendritic cells. J. Exp. Med. 201, 1899–1903 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Akbari, O., DeKruyff, R.H. & Umetsu, D.T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2, 725–731 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, X. et al. Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3. Mol. Cell. Biol. 24, 5106–5118 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee, H., Rezai-Zadeh, N. & Seto, E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol. Cell. Biol. 24, 765–773 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rezai-Zadeh, N. et al. Histone deacetylases: purification of the enzymes, substrates, and assay conditions. Methods Enzymol. 377, 167–179 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Gao, L., Cueto, M.A., Asselbergs, F. & Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748–25755 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Lucas, M., Zhang, X., Prasanna, V. & Mosser, D.M. ERK activation following macrophage FcγR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175, 469–477 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Tone, M., Powell, M.J., Tone, Y., Thompson, S.A.J. & Waldmann, H. IL-10 gene expression is controlled by the transcription factors Sp1 and Sp3. J. Immunol. 165, 286–291 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Reuss, E. et al. Differential regulation of interleukin-10 production by genetic and environmental factors - a twin study. Genes Immun. 3, 407–413 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Suzuki, M., Yamada, T., Kihara-Negishi, F., Sakurai, T. & Oikawa, T. Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression. Oncogene 22, 8688–8698 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Bradbury, C.A. et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 19, 1751–1759 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. West, A.G. & Fraser, P. Remote control of gene transcription. Hum. Mol. Genet. 14, R101–R111 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Im, S.-H., Hueber, A., Monticelli, S., Kang, K.-H. & Rao, A. Chromatin-level regulation of the IL10 gene in T cells. J. Biol. Chem. 279, 46818–46825 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Kirberg, J. et al. Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J. Exp. Med. 180, 25–34 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Vicente-Suarez, I. et al. Identification of a novel negative role of flagellin in regulating IL-10 production. Eur. J. Immunol. 37, 3164–3175 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Villagra, A. et al. Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression. J. Biol. Chem. 282, 35457–35470 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang, X.-J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol. 9, 206–218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Villagra, A. et al. Chromatin remodeling and transcriptional activity of the bone-specific osteocalcin gene require CCAAT/enhancer-binding protein β-dependent recruitment of SWI/SNF activity. J. Biol. Chem. 281, 22695–22706 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Kearney, E.R., Pape, K.A., Loh, D.Y. & Jenkins, M.K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–339 (1994).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Mice transgenic for a T cell antigen receptor specific for hemagglutinin peptide were from H. von Boehmer (Harvard University); the THP-1 cell line was provided by A. List (H. Lee Moffitt Cancer Center). Supported by the US Public Health Service (CA78656 and CA87583 to E.M.S.).

Author information

Authors and Affiliations

Authors

Contributions

A.V. did ChIP, quantitative real-time RT-PCR, cloning of reporter genes and reporter gene assays, overexpression of HDAC proteins and generation of stable cell lines lacking HDAC11, designed the overall project and prepared part of the manuscript; F.C. isolated B cells and T cells and did ELISAs, tolerance experiments and flow cytometry; H.-W.W. provided technical and experimental support for B cell and T cell isolation, ELISA and tolerance experiments; I.S. provided technical and experimental support for the overexpression of HDAC proteins and quantitative real-time RT-PCR; M.G. cloned mutant HDAC11; M.M. purified adenovirus encoding GFP and HDAC11; D.N. provided technical and experimental assistance for the cloning of reporter genes and reporter gene assays; K.L.W., P.W.A., K.B. and J.P.-I. helped design experiments, provided reagents and discussed the project throughout; and E.M.S. directed the project, designed the overall project, oversaw all experiments, secured funding and was mainly responsible for manuscript writing.

Corresponding authors

Correspondence to Alejandro Villagra or Eduardo M Sotomayor.

Ethics declarations

Competing interests

P.W.A. is an employee of Novartis Institutes for Biomedical Research.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Table 1 and Supplementary Methods (PDF 2042 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Villagra, A., Cheng, F., Wang, HW. et al. The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol 10, 92–100 (2009). https://doi.org/10.1038/ni.1673

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1673

This article is cited by

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