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Histone/protein deacetylase 3 dictates critical aspects of regulatory T cell development and function

Cellular & Molecular Immunology volume 13, pages 415–417 (2016)Cite this article

Regulatory T cells (Tregs) comprise a subset of CD4+ T lymphocytes that holds promise as immunotherapy for inflammatory disease states including autoimmune disorders, solid organ allograft rejection, graft-versus-host disease, and acute inflammatory conditions1. However, limited availability of Treg numbers restricts their usefulness in cell transfer applications, particularly as patients may need multiple infusions for chronic diseases. Pharmacologic manipulation of the Treg lineage – either as part of an ex vivo expansion strategy or via drugs administered to a patient – may augment the Treg suppressive effect, stabilize a regulatory phenotype, and ultimately promote immune homeostasis. Conversely, adjunctive drug therapy that diminishes Treg function could benefit malignant diseases in which anti-tumor immunity prevents metastasis and promotes tumor clearance. Epigenome-modifying drugs represent an attractive pharmacotherapeutic strategy because of their profound effects on Treg phenotype and function. For example, pan-histone/protein deacetylase inhibitors (pan-HDACi) augment Treg numbers and suppressive function in part by promoting acetylation of FOXP3 – the master Treg transcription factor – and enhancing DNA binding2. In a recent issue of the Journal of Clinical Investigation, Wang and colleagues published unexpected results determining that histone/protein deacetylase 3 (HDAC3) is critical for Treg development and function3. Their results carry important implications for translating Treg epigenetic mechanisms into the clinical arena and raise interesting questions about biologic control of Treg function.

Because pan-HDACi display narrow therapeutic indices when administered systemically4, investigators have developed intense interest in which HDAC isoforms could be targeted to achieve a desired effect on Treg phenotype and function. Of the 11 classical zinc-dependent HDAC metalloenzymes, most available data describe the effects of class IIa HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) on Treg biology. For example, knockdown of HDAC7 and HDAC9 can augment Treg suppressive function4. However, class IIa HDACs have weak histone/protein deacetylase activity owing to a histidine rather than a tyrosine residue in their catalytic domain5. Rather than acting via an enzymatic mechanism, class IIa HDACs may exert their effects by functioning as bromodomains (protein domains that recognize acetylated lysine residues) in complex with class I HDACs such as HDAC36,7.

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  1. Johns Hopkins University Division of Pulmonary and Critical Care Medicine, Baltimore, MD, USA

    Benjamin D Singer & Franco R D’Alessio

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  1. Benjamin D Singer
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  2. Franco R D’Alessio
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Correspondence to Franco R D’Alessio.

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Singer, B., D’Alessio, F. Histone/protein deacetylase 3 dictates critical aspects of regulatory T cell development and function. Cell Mol Immunol 13, 415–417 (2016). https://doi.org/10.1038/cmi.2015.51

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