Histone deacetylase function in CD4+ T cells

An Author Correction to this article was published on 12 March 2019

This article has been updated

Abstract

The differentiation of T helper cell subsets and their acquisition of effector functions are accompanied by changes in gene expression programmes, which in part are regulated and maintained by epigenetic processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators that function by mediating dynamic changes in the acetylation of histones at lysine residues. In addition, many non-histone proteins are also acetylated, and reversible acetylation affects their functional properties, demonstrating that HDACs mediate effects beyond the epigenetic regulation of gene expression. In this Review, we discuss studies revealing that HDACs are key regulators of CD4+ T cell-mediated immunity in mice and humans and that HDACs are promising targets in T cell-mediated immune diseases. Finally, we discuss unanswered questions and future research directions to promote the concept that isoform-selective HDAC inhibitors might broaden the clinical application of HDAC inhibitors beyond their current use in certain types of cancer.

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Fig. 1: Chromatin-mediated control of gene expression by reversible lysine acetylation.
Fig. 2: Structure and intracellular localization of human HDACs.
Fig. 3: Impact of reversible lysine acetylation on non-histone target proteins.
Fig. 4: Overview of the roles of HDACs during T cell development and peripheral T helper cell subsets.
Fig. 5: Selected examples of (simplified) molecular mechanisms of how HDAC family members control T helper cell differentiation and effector function.

Change history

  • 12 March 2019

    In Table 1 in the originally published version of this article, the phenotype of Hdac1-cKO CD8+ T cells (3rd row) was incorrectly described. This has been corrected in the HTML and PDF versions of the manuscript.

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Acknowledgements

The authors apologize to those colleagues whose work could not be cited owing to space limitations. Within the past few years, the work in the laboratory of W.E. has been funded by the Austrian Science Fund (P14261, P16708, P19930, P23641, P26193, P29790, I00698, Y163 and SFB F23), the European Union (EU) Horizon 2020 Marie Sklodowska Curie programme (grant agreement 675395) and the Austrian Science Fund–MedUni Wien PhD programme Inflammation and Immunity (W1212). The work in the laboratory of C.S. has been funded by the Austrian Science Fund (P28705, P28034, P26193, P25807, P16443, P14909, P13638 and P13068) and the Austrian Science Fund PhD programmes W1220 and W1261. W.E. and C.S. were also funded by a joint grant of the Vienna Science and Technology Fund (WWTF) through project LS09-031.

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Nature Reviews Immunology thanks W. Hancock and the other anonymous reviewer(s) for their assistance with the peer review of this manuscript.

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Glossary

Nucleosome

The basic structural subunit of chromatin, which consists of ~147 bp DNA wrapped around an octamer of histones.

ε-Amino group

The functional group of the amino acid lysine, which is frequently targeted by modifications including acetylation and other acylations, methylation, ubiquitylation and sumoylation. The ε-amino group is positively charged, but it loses its charge upon acetylation.

Histone code

A regulatory system allowing the control of chromatin accessibility and expression of genes by combinations of post-translational histone modifications including acetylation, methylation, phosphorylation, ubiquitylation, methylation, sumoylation and ADP-ribosylation. These modifications serve as docking sites for reader proteins, leading to the recruitment of protein complexes that alter chromatin structure and thus the transcription of target genes.

Epigenetic readers

Proteins that recognize and bind specifically to modified histones and other modified proteins. These proteins usually have specific domains such as bromodomains for reading acetylation marks or chromodomains for reading methylation marks. Alternatively, certain readers specifically bind to histone tails only in the absence of the modification.

Bromodomains

Protein domains that are ~70–110 amino acids in length and that recognize lysine acetylation marks on histone proteins. Bromodomains are present in some histone acetyltransferases and are also found in factors that recruit either chromatin remodelling complexes to target sites or basal transcription factors to gene promoters.

YEATS domains

Named after their five founding domain-containing proteins (YAF9, ENL, AF9, TAF14 and SAS5), these protein domains are ~80 amino acids in length and recognize lysine acetylation or crotonylation marks on histones.

Plant homeodomain

(PHD). A protein domain that is ~50–80 amino acids in length and that recognizes lysine methylation and lysine acetylation marks. PHDs are present in reader proteins, which include the histone acetyltransferase p300 and CREB-binding protein (CBP).

Epigenetic writers

Enzymes such as histone acetyltransferases and histone methyltransferases that add post-translational modifications on histones.

Epigenetic erasers

Enzymes that remove histone modifications. This group of proteins includes histone deacetylases and histone demethylases.

NCOR1–SMRT co-repressor

A complex formed by two factors (nuclear receptor co-repressor 1 (NCOR1) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)) that are transcriptional co-repressors; the complex bridges gene-specific transcription factors, such as nuclear receptors or members of the BTB domain zinc-finger transcription family, with chromatin modifying enzymes. Histone deacetylase 3 (HDAC3) is the major HDAC member recruited by NCOR1 complexes.

SWI/SNF complex

(Switch/sucrose non-fermentable complex). A highly conserved multiprotein complex with ATPase activity. The SWI/SNF complex, which is also known as the BRG1/BRM associated factor (BAF) complex has chromatin remodelling function, that is, it changes the accessibility of specific chromatin regions by moving, ejecting or restructuring nucleosomes.

Tonic signalling

Low-level, constitutive antigen receptor signalling in B and T cells in the basal state. This signalling is essential for the survival of B cells and the maintenance of peripheral T cell fitness. It is also implicated in maintaining T cell tolerance.

Experimental autoimmune encephalomyelitis

(EAE). An (auto)inflammatory disease in mice induced by injecting myelin basic protein or peptides derived from myelin oligodendrocyte glycoprotein or proteolipid protein together with complete Freund’s adjuvant and pertussis toxin. EAE is characterized by paralysis and inflammation and demyelination in the central nervous system and is a model of human multiple sclerosis.

Invariant natural killer T cells

(iNKT cells). A subset of natural killer T (NKT) cells that express a T cell receptor (TCR) with an invariant Vα14–Jα18 (in mice) or Vα24–Jα18 (in humans) TCR α-chain paired with a restricted subset of TCR Vβ chains. iNKT cells exclusively recognize glycolipid antigens that are presented on CD1d molecules and rapidly produce cytokines after activation.

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Ellmeier, W., Seiser, C. Histone deacetylase function in CD4+ T cells. Nat Rev Immunol 18, 617–634 (2018). https://doi.org/10.1038/s41577-018-0037-z

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