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

Nature Immunology volume 10, pages 92–100 (2009)Cite this article

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.

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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.

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.

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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.).

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Authors and Affiliations

  1. Division of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, Florida, USA

    Alejandro Villagra, Fengdong Cheng, Hong-Wei Wang, Ildelfonso Suarez, Michelle Maurin, Danny Nguyen, Kenneth L Wright, Javier Pinilla-Ibarz & Eduardo M Sotomayor

  2. Cancer Biology PhD Program, University of South Florida, Tampa, 33612, Florida, USA

    Ildelfonso Suarez

  3. Division of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, Florida, USA

    Michelle Glozak, Edward Seto & Eduardo M Sotomayor

  4. Department of Oncological Sciences, University of South Florida, Tampa, 33612, Florida, USA

    Michelle Glozak, Kenneth L Wright, Javier Pinilla-Ibarz, Edward Seto & Eduardo M Sotomayor

  5. Novartis Institutes for Biomedical Research, Cambridge, 02139, Massachusetts, USA

    Peter W Atadja

  6. Medical College of Georgia, Augusta, 30912, Georgia, USA

    Kapil Bhalla

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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.

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Competing interests

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

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

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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

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