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Review
. 2009 Dec;8(12):969-81.
doi: 10.1038/nrd3031. Epub 2009 Oct 26.

V体育官网 - Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells

Liqing Wang  1 , Edwin F de Zoeten, Mark I Greene, Wayne W Hancock
Affiliations
Review

"V体育ios版" Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells

Liqing Wang (VSports在线直播) et al. Nat Rev Drug Discov. 2009 Dec.

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 VSports手机版. 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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Figures

Figure 1
Figure 1. Main anti-inflammatory effects of histone deacetylase inhibitors (HDACls) in leukocytes
Key pathways for differentiation of activated CD4+ T cells are shown, along with lineage-specific transcription factors (T-bet, GATA-3, RORγt and FOXP3). HDACI use decreases the production of proteins shown in red boxes. Many anti-inflammatory effects of HDACIs are mediated through effects on antigen-presenting cells (APCs), including dendritic cells and monocytes. HDACI-induced suppression of the production of multiple cytokines impairs the differentiation of CD4+ T cells into TH1 cells characterized by T-bet expression and TH17 cells characterized by RORγt expression. However, HDACI treatment does not impair development of TH2 cells expressing GATA-3 or regulatory T cells (Tregs) expressing FOXP3. HDACI use also prevents the conversion of Tregs into TH17 cells. The effects of HDACIs on other leukocytic cell types, including granulocytes, natural killer cells and non-malignant B cells, are poorly understood. CCR, C-C receptor; CD, cluster of differentiation; IFN, interferon; IL, interleukin; IP-10, inducible protein-10; I-TAC, inducible-T-cell activating chemokine; MCP, monocyte chemoattractant protein; Mig, monokine induced by interferon γ; S1P, sphingosine-1-phosphate; TGF, transforming growth factor; TNF, tumour necrosis factor; TLR, Toll-like receptor.
Figure 2
Figure 2. HDAC/FOXP3 complex in regulatory T cells
Within the nucleus, the forkhead transcription factor FOXP3 undergoes homo- and hetero-oligomerization (the latter with FOXP1) and recruits the histone acetyl transferase (HAT) TIP60 and the class IIa histone deacetylase (HDAC) HDAC7 to a region between 100 and 200 amino acids from the amino-terminus. FOXP3 binding to DNA is impaired by its interaction with a second class IIa HDAC, HDAC9, that acts as a scaffold for assembly of a complex that includes DNA methyltransferase 1 (DNMT1), a class I HDAC (for example, HDAC3), methyl-binding domain 2 (MBD2) and co-repressor complexes, for example, silencing mediator of retinoid and thyroid hormone receptors/nuclear hormone receptor co-repressor (SMRT/NCoR). T cell receptor (TCR) stimulation activates one or more kinases that phosphorylate class II HDACs; candidate kinases include protein kinase D (PKD), calcium/calmodulin-dependent kinase (CaMK) and salt-inducible kinase (SIK). Phosphorylation of HDAC9 acts as an ‘off’ switch, as phosphorylated HDAC9 undergoes a conformational change and dissociates from FOXP3, removing inhibitory complexes and leading to de-repression of FOXP3 and its interaction with other proteins (for example, myocyte enhancing factor 2 (MEF2)) and DNA. Phosphorylated HDAC9 is exported from the nucleus in conjunction with the exportin 14-3-3. In the cytoplasm, phosphorylated HDAC9 is either degraded by the proteasome or might be dephosphorylated and re-enter the nucleus to re-establish binding to FOXP3, limiting its action again (‘on’ switch). Upon removal of HDAC9 and its associated inhibitory complexes, FOXP3 is acetylated by one or more HATs, for example, PCAF and p300, and binds to the promoter regions of target genes in the DNA. Ac denotes acetylation; P denotes phosphorylation.
Figure 3
Figure 3. HDAC6 and HDAC9 as synergistic targets for Treg-based histone deacetylase inhibitor (HDACI) therapy
In the presence of functional HDAC6, heat shock protein 90 (HSP90) exists in a state of basal acetylation and binds multiple client proteins, including heat shock factor HSF1 (1). With inhibition of HDAC6, HSP90 acetylation is markedly enhanced by the actions of one or more unknown histone acetyl transferases and client proteins are released. Whereas many client proteins undergo ubiquitination and proteasomal degradation, others, including HSF1, are functional (2). HDAC9 and SIRT1 may bind HSF1 and differentially maintain its deacetylation (3). Inhibition of HDAC9 promotes HSF1 acetylation, probably by p300, and its trimerization (4). Trimeric HSF1 undergoes phosphorylation by POLO1 or other kinases and nuclear translocation to induce the expression of other heat shock proteins such as HSP70 and HSP27 (5). HSF1-induced HSP70 binds to and serves as a chaperone for many proteins, including FOXP3 (6). HSP70 may promote the maturation of newly synthesized FOXP3 and possibly nuclear translocation and DNA interactions (7). Ac denotes acetylation.
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References

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