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Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells

Nature Reviews Drug Discovery volume 8, pages 969–981 (2009)Cite this article

Key Points

  • Histone deacetylases (HDACs) regulate gene expression and protein function by catalysing the removal of acetyl groups from the lysines of histone tails and a large number of signalling molecules and other non-histone proteins. Much effort has gone into development of HDAC inhibitors (HDACIs), especially for applications in oncology.

  • Accruing studies indicate that HDACI therapy might also be of use in non-oncology settings, including during inflammation and autoimmunity. Most of these studies have employed a one-size-fits-all approach and used pan-HDACIs. Pan-HDACI use can limit dendritic cell differentiation and curb dendritic cell and T cell activation, resulting in beneficial effects in experimental models of arthritis, inflammatory bowel disease and transplant rejection. Initial clinical trials, including some in Phase II, are also showing evidence of HDACI tolerability, safety and efficacy.

  • A subset of T lymphocytes expressing the transcription factor, FOXP3, are of increasing interest as these so-called regulatory T cells (Tregs) limit inflammation and autoimmunity in humans and experimental animals. Recently, FOXP3 itself was shown to be regulated by acetylation by histone acetyltransferases, and deacetylation by HDACs. Exposure to pan-HDACIs increases FOXP3+ Treg production, Foxp3 acetylation and Treg suppressive functions in vitro and in vivo.

  • Experimental studies indicate that a subset of HDAC proteins, especially of the class II family of HDACs, is of particular relevance to control of Treg functions. Several studies have pointed to the value of targeting HDAC7 and HDAC9 (class IIa HDAC) and also HDAC6 (class IIb). Development of selective pharmacological inhibitors of individual HDACs, or associated interacting proteins, may provide significant benefits compared with use of pan-HDACIs.

  • Ongoing analysis of HDAC structure–function relationships and the development of new and selective HDACIs have the promise of providing powerful new therapies for immuno-inflammatory disorders.

Abstract

Classical zinc-dependent histone deacetylases (HDACs) catalyse the removal of acetyl groups from histone tails and also from many non-histone proteins, including the transcription factor FOXP3, a key regulator of the development and function of regulatory T cells. Many HDAC inhibitors are in cancer clinical trials, but a subset of HDAC inhibitors has important anti-inflammatory or immunosuppressive effects that might be of therapeutic benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of HDAC inhibitors to enhance the production and suppressive functions of FOXP3+ regulatory T cells. Understanding which HDACs contribute to the regulation of the functions of regulatory T cells may further stimulate the development of new class- or subclass-specific HDAC inhibitors with applications beyond oncology.

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Figure 1: Main anti-inflammatory effects of histone deacetylase inhibitors (HDACIs) in leukocytes.
Figure 2: HDAC/FOXP3 complex in regulatory T cells.
Figure 3: HDAC6 and HDAC9 as synergistic targets for Treg-based histone deacetylase inhibitor (HDACI) therapy.

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Authors and Affiliations

  1. Division of Transplant Immunology, Children's Hospital of Philadelphia, Philadelphia, 19104, USA

    Liqing Wang, Edwin F. de Zoeten & Wayne W. Hancock

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Philadelphia, 19104, USA

    Mark I. Greene & Wayne W. Hancock

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  1. Liqing Wang
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  2. Edwin F. de Zoeten
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Correspondence to Wayne W. Hancock.

Glossary

Histone deacetylase

(HDAC). Enzyme that catalyses removal of acetyl groups from lysines in histone tails or non-histone proteins; such deacetylation usually decreases gene expression or protein function. Classical HDACs are those which are zinc-dependent and include HDACs 1–11. Sirtuins are a distinctly different family of HDACs (SIRT1–7) that are NAD-dependent and are mainly involved in cell metabolism.

FOXP3

Forkhead or winged helix transcription factor that is expressed primarily in regulatory T cells and controls their functions; its DNA binding and interactions with other proteins are promoted by acetylation and impaired by deacetylation. Mutations in FOXP3 are responsible for life-threatening autoimmunity in patients and experimental animals.

Regulatory T cell

(Treg). These cells express FOXP3 and dampen immune responses mediated by T and B cells. They may also modulate functions of cells of the innate immune system. They function by multiple mechanisms, including direct membrane–membrane effects, the release of soluble products and catabolism of essential amino acids.

Histone acetyltransferase

(HAT). Enzymes that catalyse acetylation of key lysines in histone tails and various non-histone proteins; such acetylation usually promotes gene expression or protein function.

Aggresome

An intracellular inclusion body that stores misfolded intracellular proteins and recruits motor proteins to transport misfolded or aggregated proteins to chaperones and proteasomes for subsequent destruction.

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Wang, L., de Zoeten, E., Greene, M. et al. Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells. Nat Rev Drug Discov 8, 969–981 (2009). https://doi.org/10.1038/nrd3031

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