CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2

Boucheron, Nicole; Tschismarov, Roland; Göschl, Lisa; Moser, M.; Lagger, Sabine; Sakaguchi, Shoji; Winter, Mircea; Lenz, F.; Vitko, Dijana; Breitwieser, Florian P.; Müller, Lena; Hassan, Hammad; Bennett, Keiryn L.; Colinge, Jacques; Schreiner, Wolfgang; Egawa, Takeshi; Taniuchi, Ichiro; Matthias, Patrick; Seiser, Christian; Ellmeier, Wilfried

doi:10.1038/ni.2864

Cited by 70 publications

(78 citation statements)

References 45 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We investigated the role of histone deacetylase-3 (HDAC3) in T cell development using CD2-icre conditional knockout (HDAC3-cKO) mice. Although T cells co-express several HDAC family members during development (1, 49, 50), HDAC3 has a unique role as conditional deletion of HDAC3 led to a block in T cell development at the DP stage due to an inability to undergo positive selection. The block in T cell development could not be rescued by an OT-II TCR transgene.…”

Section: Discussionmentioning

confidence: 99%

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

Philips

Chen

McWilliams

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Philips

Chen

McWilliams

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Although the Cd8 locus is methylated (69, 70) and subject to histone modifications (71), and although there is evidence for epigenetic control of its expression (71, 72), whether there is a similar ‘imprint’ of thymic events on post-thymic Cd8 gene expression remains to be determined. In fact, the current evidence points to a greater control by the transcriptional circuitry: Runx3 is important to sustain expression of Cd8 in CD8 + T cells effectors (72), whereas, as we will see below, Thpok is critical for its repression in CD4 + T cells (47, 68, 73).…”

Section: Control Of Cd4 Expression In Mature T Cells: An Epigenetic Epicmentioning

confidence: 99%

“…It is also important to emphasize that, as illustrated by a recent study of histone deacetylase (HDAC) functions in T cells (71), epigenetic and active transcriptional control collaborate to maintain appropriate gene expression. Acetylation of histone H3 on lysine residues 9 and 27, typically at gene promoters and enhancers, is associated with increased transcriptional activity (88).…”

Section: Thpok Vs Runx3 In Mature T Cells: the Circuitry Strikes Backmentioning

confidence: 99%

“…HDACs are part of large transcriptional repression complexes, some of which associate with members of the BTB zinc finger family (41, 89) and their recruitment dampens gene expression. Inactivation of both HDAC1 and HDAC2 in the thymus causes the conversion of CD4 + effectors into CD4 + CD8 + cells expressing cytotoxic genes and Runx3, and producing IFNγ (71). Accordingly, activated CD4 + T cells from HDAC1 and HDAC2 deficient mice show increased H3K9 acetylation at the promoters of cytotoxic genes and at a Cd8 enhancer active in effector cells.…”

Section: Thpok Vs Runx3 In Mature T Cells: the Circuitry Strikes Backmentioning

confidence: 99%

See 1 more Smart Citation

What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4+–CD8+ Lineage Commitment Transcriptional Circuitry To Control Their Function

Vacchio

Bosselut

2016

The Journal of Immunology

View full text Add to dashboard Cite

MHC-restricted CD4+ and CD8+ T cell are at the core of most adaptive immune responses. Although these cells carry distinct functions, they arise from a common precursor during thymic differentiation, in a developmental sequence that matches CD4 and CD8 expression and functional potential with MHC restriction. While the transcriptional control of CD4+-CD8+ lineage choice in the thymus is now better understood, less was known about what maintains the CD4+- and CD8+-lineage integrity of mature T cells. In this review, we discuss the mechanisms that establish in the thymus, and maintain in post-thymic cells, the separation of these lineages. We focus on recent studies that address the mechanisms of epigenetic control of Cd4 expression and emphasize how maintaining a transcriptional circuitry nucleated around Thpok and Runx proteins, the key architects of CD4+-CD8+ lineage commitment in the thymus, is critical for CD4+ T cell helper functions.

show abstract

“…HDAC9 was reported to induce inflammatory gene expression in macrophages and prevent polarization to anti-inflammatory M2 phenotype 52 . 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 .…”

Section: Hdacs and Inflammationmentioning

confidence: 99%

Histone Deacetylases and Cardiometabolic Diseases

Yiew

Chatterjee

Hui

et al. 2015

ATVB

View full text Add to dashboard Cite

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.

show abstract

CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2

Cited by 70 publications

References 45 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

What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4+–CD8+ Lineage Commitment Transcriptional Circuitry To Control Their Function

Histone Deacetylases and Cardiometabolic Diseases

Contact Info

Product

Resources

About