Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells

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Lysine ɛ-acetylation is a post-translational modification that alters the biochemical properties of many proteins. The reaction is catalyzed by histone/protein acetyltransferases (HATs), and is reversed by histone/protein deacetylases (HDACs). As a result, HATs and HDACs constitute an important, though little recognized, set of proteins that control the functions of T-regulatory (Treg) cells. Targeting certain HDACs, especially HDAC6, HDAC9, and Sirtuin-1 (Sirt1), can augment Treg suppressive potency by several distinct and potentially additive mechanisms. These involve promoting Forkhead box p3 (Foxp3) gene expression and preserving Foxp3 lysine ɛ-acetylation, which infers resistance to ubiquitination and proteasomal degradation, and increases DNA binding. Moreover, depleting certain HDAC can enhance the heat shock response, which increases the tenacity of Treg to survive under stress, and helps preserve a suppressive phenotype. As a result, HDAC inhibitor therapy can be used to enhance Treg functions in vivo and have beneficial effects on allograft survival and autoimmune diseases.

Highlights

HATs and HDACs control lysine acetylation, an important post-translational modification in histone and non-histone proteins. ► Acetylation of Foxp3 in Tregs increases both its DNA binding and resistance to proteasomal degradation. ► Foxp3 transcription factors are regulated by acetylation (p65, STAT5) or indirectly by HDAC/HAT dependent mediators (SMAD3). ► Targeting HDAC6 or HDAC9 increases HSR gene expression which protects Treg from stress and preserves a suppressive phenotype.

Introduction

The ability to control the immune response is an important therapeutic goal in the management of many diseases. However, doing so requires finding a delicate balance between activation and attenuation. Unfortunately, most current therapeutic strategies targeting the immune system have relatively limited antigen specificity and therefore notoriously lack precision. For example, immune modulation after solid organ transplantation faces the challenge of achieving enough suppression to limit graft rejection without impairing the host's ability to protect against infections [1] and malignancy [2]. This comes in addition to numerous non-immune toxicities [3]. Treatments for autoimmune conditions like inflammatory bowel disease face very similar problems [4]. Conversely, at the opposite end of the spectrum, cancer immunotherapy, while very promising and increasingly effective against a wide range of tumors, can predispose to autoimmunity [5]. Throughout the search for more specific approaches, T-regulatory (Treg) cells have been recognized as an important T cell subset able to limit immune responses in an antigen-specific manner, and are crucial to maintaining self-tolerance [6, 7•]. Treg-based therapies, such as ex vivo expansion or efforts to enhance in vivo suppressive function offer a potential avenue towards more antigen directed immunosuppression [8], and Tregs are now recognized as an obstacle and therapeutic target in anti-neoplastic treatments [9]. The best established and most studied type of Treg cells are characterized by expression of the transcription factor forkheadbox-p3 (Foxp3), which plays a key role in their development and functions [10, 11]. HDAC inhibitor (HDACi) use can augment Foxp3+ Treg production and induce various molecular changes that enhance their phenotype [12]. As a result, the suppressive capacity of murine [13], non-human primate [14] and human [15••] Tregs can be increased by treatment with histone/protein deacetylase inhibitors (HDACi) [16, 17•], with therapeutic consequences in models of autoimmunity and transplantation [18, 19••, 20••, 21••]. At present, several histone/protein acetyltransferases (HATs) and histone/protein deacetylases (HDACs) have been implicated in Treg biology, and the relevant HDAC biology is summarized Figure 1. Aspects of this work are summarized in the following sections, with an emphasis on the lead HDAC and HAT molecular pathways that are known to influence Treg function in vivo as well as in vitro.

Section snippets

Acetylation of Foxp3 prevents proteasomal degradation and increases Treg potency

Post-translational modifications expand the regulatory potential of proteins vastly beyond mere gene expression. Lysine (K) provides one of the most reactive residues that can engage in a myriad of biochemical alterations [22]. ɛ-amino acetylation can neutralize lysine's positive charge (Figure 2) and profoundly alter the biological functions of affected proteins [23, 24••]. Historically, lysine acetylation was first appreciated in regard to post-translational modifications of histone tail

HDACs alter transcription factors of the Foxp3 gene

Since the discovery of Foxp3+ Tregs and appreciation of their significance, investigators have sought to understand the mechanisms of Foxp3 gene regulation. In 2006, Mantel et al. identified the Foxp3 promoter region and reported several binding sites for the transcription factors NFAT and AP-1 [33]. Subsequently, Zorn et al. reported IL-2 dependent STAT5 as another transcription factor relevant to Foxp3 gene expression [34]. Additional transcription factors were implicated based on insights

Foxp3 gene methylation and histone acetylation

Over the past few years, increasing attention was dedicated to understanding methylation of the Foxp3 promoter and conserved non-coding sequences (CNS) within the Foxp3 gene [58, 59]. Methylation of CpG islands and acetylation of histones determine accessibility of the DNA through chromatin remodeling. Of note, Zheng et al. found that three CNS within the Foxp3 gene convey lineage stability of the Treg phenotype through their methylation state and responsiveness to transcription Foxp3 factors [

HDAC influence on the heat shock response

Not only pan-HDACi, but also HDAC6 and HDAC9 specific targeting, can augment activation of heat shock response (HSR) gene transcription in Treg cells [20••, 21••]. The HSR enables the expression of chaperone proteins that alleviate and counter the sequelae of cellular stress, and is primarily induced through DNA binding of heat shock transcription factor-1 (HSF1) to heat shock elements in the regulatory regions of many genes. Under resting conditions, the majority of HSF1 monomer is inactive

Additional considerations and conclusions

We are currently assembling evidence showing that several additional HDACs, beyond HDAC6, HDAC9 and Sirt1, have biologically relevant effects on Foxp3-dependent Treg biology. There are also, of course, numerous additional post-translational and epigenetic mechanisms beyond protein acetylation and DNA methylation that are relevant to modulation of Foxp3+ Treg function. We have recently reported evidence of the key role of proteolytic cleavage so as to generate a form of Foxp3 that appears most

Disclosure

The authors have no financial conflicts of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by the National Institute of Allergy and Infectious Diseases (K08AI095353 to U.H.B., and AI073489 to W.W.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

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