Three Novel Acetylation Sites in the Foxp3 Transcription Factor Regulate the Suppressive Activity of Regulatory T Cells

Kwon, Hye-Sook; Lim, Hyung W.; Wu, Jessica J; Schnölzer, Martina; Verdin, Eric; Ott, Melanie

doi:10.4049/jimmunol.1100903

Cited by 141 publications

(129 citation statements)

References 52 publications

(74 reference statements)

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“…Ubiquitylation of FOXP3, RORγt and T-bet controls transcription factor stability, and dysregulation of the ubiquitylating or de-ubiquitylating enzymes can induce phenotypic plasticity in these cells [183][184][185] . Blocking the activity of sirtuin 1 preserves FOXP3 acetylation, enhancing FOXP3 stability and T Reg cell function 186,187 , whereas inhibition of sirtuin 1 increases RORγt acety lation in T H 17 cells, which impedes RORγt activity 188 , thus creating another therapeutically exploitable dichotomy between inflammatory and regulatory cells.…”

Section: Gene Expression Regulationmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Gene Expression Regulationmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…Reduced Foxp3 expression was observed in PBMCs from elderly asthmatics [88]. There is an important role for acetylation and deacetylation of Foxp3 in the regulation of this transcription factor [89,90] including on K31, K262 and K267 [91]. It has been identified that p300 and Tip60 can acetylate Foxp3 (intriguingly, p300 and Tip60 work together to acetylate one another and Foxp3) [92].…”

Section: Tregs: Regulation Of the Foxp3 Transcription Factor Acetylatmentioning

confidence: 99%

“…Increased Treg suppressive function (in combination and alone) EX-527 increased acetylation of K31, K262 and K267, and increased the stability and levels of the transcription factor [91,96] Foxp3/Tregs HDAC1-3 inhibitor MS-275 Ambiguous effects [98][99][100] RORγt/Th17 HDAC1-3 inhibitor MS-275 Enhanced Th17 differentiation in mouse splenocytes [106] RORγt/Th17 Pan HDACi givinostat Downregulated the IL-6 receptor on T cells that reduced their ability to differentiate into Th17 cells, but instead skewed differentiation toward the Treg phenotype [107] Foxp3 and RORγt Pan HDACi TSA Increased Foxp3 and decreased RoRγt levels in an ovalbumin challenge asthma mouse model [38] HDAC: Histone deacetylase; HDACi: Histone deacetylase inhibitor; PBMC: Peripheral blood mononuclear cell; TSA: Trichostatin A.…”

Section: Macrophages: Selective Regulation Of the Nf-κb Transcriptionmentioning

confidence: 99%

“…There has also been interest in the development of novel HDAC6i for augmentation of Treg-suppressive function [97]. Furthermore, Sirt1 inhibitor EX-527 was used in a study where acetylation sites were identified on Foxp3 (K31, K262 and K267), and increased acetylation of these lysines as well as the stability and levels of the transcription factor [91]. HDAC1-3 inhibitor MS-275 increased Foxp3 expression in T cells isolated from human blood [98].…”

Section: Tregs: Regulation Of the Foxp3 Transcription Factor Acetylatmentioning

confidence: 99%

“…This illustrates that individual HDACs have specific roles in the control of anti-inflammatory IL10 expression (with HDAC11 as an interesting possible target due to its inhibitory role in IL10 expression), and in the inhibition of CXCL8 expression by IL-10 in these cells. NF-κB/macrophages HDAC1-3 inhibitor MS-275 Ambiguous effects [66][67][68][69][70][71] NF-κB/macrophages HDAC3 inhibitor RGFP966 Attenuation of Inflammation [74] GATA3/Th2 cells SIRT1 inhibitor Sirtinol Increased Th2 related expression in T cells from cord blood; and in PBMCs from severe asthmatics Enhanced acetylation and activity of the GATA3 transcription factor in HUT78 T lymphocytes [83] GATA3/Th2 cells SIRT1 activator (SRT2172) Reduced IL-4 mRNA expression in PBMCs from ten patients with severe asthma [83] Foxp3/Tregs HDAC6i ACY-738 and SIRT1 inhibitor EX-527Increased Treg suppressive function (in combination and alone) EX-527 increased acetylation of K31, K262 and K267, and increased the stability and levels of the transcription factor [91,96] Foxp3/Tregs HDAC1-3 inhibitor MS-275 Ambiguous effects [98][99][100] RORγt/Th17 HDAC1-3 inhibitor MS-275 Enhanced Th17 differentiation in mouse splenocytes [106] RORγt/Th17 Pan HDACi givinostat Downregulated the IL-6 receptor on T cells that reduced their ability to differentiate into Th17 cells, but instead skewed differentiation toward the Treg phenotype [107] Foxp3 and RORγt Pan HDACi TSA Increased Foxp3 and decreased RoRγt levels in an ovalbumin challenge asthma mouse model [38] …”

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Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

et al. 2017

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Asthma and chronic obstructive pulmonary disease are inflammatory airway diseases for which alternative therapeutic strategies are urgently needed. Interestingly, HDAC inhibitors show anti-inflammatory effects in mouse models for these diseases. Here we explore underlying mechanisms that may explain these effects. In previous studies, effects of HDAC inhibitors on histone acetylation are often correlated with their effects on gene expression. However, effects of HDAC inhibitors on transcription factors and their acetylation status may be particularly important in explaining these effects. These effects are also cell type-specific. Recent developments (including chemoproteomics and acetylomics) allow for a more detailed understanding of the selectivity of HDAC inhibitors, which will drive their further development into applications in inflammatory airway diseases. Asthma and chronic obstructive pulmonary disease (COPD) are common inflammatory airway diseases. These diseases affect millions of people world-wide, and globally, the incidence is increasing. For asthma, the clinical symptoms include among others wheezing and shortness of breath. COPD is characterized by shortness of breath upon exercise and a largely irreversible and progressive airflow limitation [1][2][3][4]. In asthma the larger airways are mainly affected, whereas in COPD, the lung parenchyma and peripheral airways are mainly affected [3]. The immunopathology of asthma and COPD is characterized by different types of inflammatory cells that are at play. For example, asthma is driven by T helper 2 (T h 2) cells, dendritic cells and is characterized by eosinophilic inflammation. In asthma there is mast-cell sensitization by immunoglobulin E (IgE), and multiple bronchoconstrictors are released [1,2]. On the other hand, COPD is characterized by T helper 1 (T h 1) cells, cytotoxic T cells and neutrophilic inflammation [5,3]. The inflammation in COPD is also characterized by increased numbers of macrophages, neutrophils and innate lymphoid cells recruited from the circulation. A variety of pro-inflammatory mediators, including cytokines, chemokines, growth factors and lipid mediators are secreted by these cell types [5]. Currently, glucocorticoids are the cornerstone in the treatment of asthma and COPD, however, this is not effective in all patients. Severe asthmatics display glucocorticoid resistance [6], and the effectivity of glucocorticoids in COPD patients is subject to debate [7,8]. Alternative therapeutic strategies are needed for these patients, which currently form a major health burden for society due to high socioeconomic costs [1][2][3][4]9]. Studying the underlying molecular mechanisms may enable the identification of new therapeutic targets. These underlying processes may include epigenetic regulation, such as lysine acetylation. Lysine acetylation is a post-translational modification of proteins, which is crucial in the regulation of cellular processes such as signal transduction and gene expression [10,11]. Lysine acetylation was initiall...

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Metabolic orchestration of T lineage differentiation and function

Yong

Moussa²,

Cretenet³

et al. 2017

FEBS Letters

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T cells are stimulated by the engagement of antigen, cytokine, pathogen, and hormone receptors. While research performed over many years has focused on deciphering the molecular components of these pathways, recent data underscore the importance of the metabolic environment in conditioning responses to receptor engagement. The ability of T cells to undergo a massive proliferation and cytokine secretion in response to receptor signals requires alterations to their bioenergetic homeostasis, allowing them to meet new energetic and biosynthetic demands. The metabolic reprogramming of activated T cells is regulated not only by changes in intracellular nutrient uptake and utilization but also by nutrient and oxygen concentrations in the extracellular environment. Notably, the extracellular environment can be profoundly altered by pathological conditions such as infections and tumors, thereby perturbing the metabolism and function of antigen-specific T lymphocytes. This review highlights the interplay between diverse metabolic networks and the transcriptional/epigenetic states that condition T-cell differentiation, comparing the metabolic features of T lymphocytes with other immune cells. We further address recent discoveries in the metabolic pathways that govern T-cell function in physiological and pathological conditions.

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Three Novel Acetylation Sites in the Foxp3 Transcription Factor Regulate the Suppressive Activity of Regulatory T Cells

Cited by 141 publications

References 52 publications

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

Metabolic orchestration of T lineage differentiation and function

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