FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Wang, Liqing; Liu, Yujie; Han, Rongxiang; Beier, Ulf H.; Akimova, Tatiana; Greene, Mark I.; Hiebert, Scott W.; Hancock, Wayne W.

doi:10.1172/jci77088

Cited by 81 publications

(67 citation statements)

References 59 publications

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“…Current and previous work demonstrates HDAC3 to be required for multiple stages in T cell development, including positive selection, peripheral T cell maturation and the generation or regulatory T cells (9, 11, 51). Utilizing different mouse models that delete HDAC3 at different stages in development (CD2-icre versus CD4-cre, Supplemental Figure 1), we have shown HDAC3 to be required for thymocyte positive selection and peripheral T cell maturation (9).…”

Section: Discussionmentioning

confidence: 99%

“…Together with different transcription factors, HDAC3 functions as the catalytic component of N-CoR/SMRT complexes to deacetylate histones at specific promoters to mediate gene silencing (6). Somatic deletion of HDAC3 leads to embryonic lethality, while tissue-specific deletion leads to hypertrophy in liver and heart (7), failure of hematopoietic stem cell maintenance (8), defects in peripheral T cell maturation (9), iNKT cell development (10), and regulatory T cell dysfunction (11). …”

Section: Introductionmentioning

confidence: 99%

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HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

Philips

Chen

McWilliams

et al. 2016

The Journal of Immunology

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To generate functional peripheral T cells, proper gene regulation during T cell development is critical. Here, we found that histone deacetylase 3 (HDAC3) is required for T cell development. T cell development in CD2-icre HDAC3 conditional knockout mice (HDAC3-cKO) was blocked at positive selection, resulting in few CD4 and CD8 T cells, and could not be rescued by a TCR-transgene. These SP thymocytes failed to upregulate Bcl-2, leading to increased apoptosis. HDAC3-cKO mice failed to downregulate RORγt during positive selection, and phenocopied the block in positive selection in RORγt-transgenic mice. In the absence of HDAC3, the RORC promoter was hyperacetylated. In the periphery, the few CD4 T cells present were skewed towards RORγt+ IL-17-producing Th17 cells, leading to inflammatory bowel disease. Positive selection of CD8SP thymocytes was restored in RORγt-KO Bcl-xl-transgenic HDAC3-cKO mice, demonstrating that HDAC3 is required at positive selection to down-regulate RORγt.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

Philips

Chen

McWilliams

et al. 2016

The Journal of Immunology

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“…Also, the suppressive functions of Foxp3 + Tregs can be profoundly affected by HDAC inhibitors (de Zoeten et al, 2010; Tao et al, 2007). Hancock et al (Wang et al, 2015) reported that deficiency of HDAC3 in Foxp3 + Tregs led to impaired Treg functions, with the subsequent development of autoimmunity, as well as a failure to induce tolerance to allografts. We provide compelling evidence that the cell surface costimulatory receptor OX40 is also a powerful regulator of Treg induction in the periphery.…”

Section: Discussionmentioning

confidence: 99%

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

et al. 2018

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SUMMARY Naive CD4+ T cells can be converted to Foxp3+ T regulatory cells (Tregs) in the periphery (iTregs), where induction of Foxp3 gene expression is central to Treg differentiation. OX40 signaling is known to inhibit Foxp3 expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress Foxp3 expression in freshly activated naive CD4+ T cells. Specifically, OX40 upregulates BATF3 and BATF, which produce a closed chromatin configuration to repress Foxp3 expression in a Sirt1/7-dependent manner. Moreover, OX40 can also activate the AKT-mTOR pathway, especially in the absence of BATF3 and BATF, to inhibit Foxp3 induction, and this is mediated by phos-phorylation and nuclear exclusion of the transcription factor Foxo1. Taken together, our results provide key mechanistic insights into how OX40 inhibits Foxp3 expression and Treg induction in the periphery.

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“…With regards to adaptive immunity, HDAC7 and HDAC2 have been reported to maintain B cell and CD4+ T cell identity, respectively 53, 54 . Interestingly, HDAC9 and HDAC3 were shown to control CD4 + Foxp3 + T regulatory (Treg) cell development and function 55, 56 . HDAC9 deficient mice exhibited enhanced expression of Foxp3, a master regulator of Treg differentiation 55 , while deletion of HDAC3 disrupted Treg cell development and function, restored IL-2 production, and upregulated pro-inflammatory IL-6 56 .…”

Section: Hdacs and Inflammationmentioning

confidence: 99%

“…Interestingly, HDAC9 and HDAC3 were shown to control CD4 + Foxp3 + T regulatory (Treg) cell development and function 55, 56 . HDAC9 deficient mice exhibited enhanced expression of Foxp3, a master regulator of Treg differentiation 55 , while deletion of HDAC3 disrupted Treg cell development and function, restored IL-2 production, and upregulated pro-inflammatory IL-6 56 . The pan-HDAC inhibitor SAHA (vorinistat) enhanced oxLDL-induced interleukin-8 and monocyte-chemoattractant protein-1 expression in human vascular endothelial cells 57 .…”

Section: Hdacs and Inflammationmentioning

confidence: 99%

Histone Deacetylases and Cardiometabolic Diseases

Yiew

Chatterjee

Hui

et al. 2015

ATVB

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Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes and cardiovascular disease. Genetic and environmental factors are linked through epigenetic mechanisms to the pathogenesis of cardiometabolic disease. Post-translational modifications of histone tails, including acetylation and deacetylation, epigenetically alter chromatin structure and dictate cell-specific gene expression patterns. The histone deacetylase (HDAC) family is comprised of 18 members that regulate gene expression by altering the acetylation status of nucleosomal histones and by functioning as nuclear transcriptional co-repressors. HDACs regulate key aspects of metabolism, inflammation, and vascular function pertinent to cardiometabolic disease in a cell- and tissue-specific manner. HDACs also likely play a role in the “metabolic memory” of diabetes, an important clinical aspect of the disease. Understanding the molecular, cellular, and physiological functions of HDACs in cardiometabolic disease is expected to provide insight into disease pathogenesis, risk factor control, and therapeutic development.

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FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Cited by 81 publications

References 59 publications

HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

Histone Deacetylases and Cardiometabolic Diseases

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