A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis

Göschl, Lisa; Preglej, Teresa; Hamminger, Patricia; Bonelli, Michael; Andersen, Liisa; Boucheron, Nicole; Gülich, Alexandra Franziska; Müller, Lena; Saferding, Victoria; Mufazalov, Ilgiz A.; Hirahara, Kiyoshi; Seiser, Christian; Matthias, Patrick; Penz, Thomas; Schuster, Michael; Bock, Christoph; Waisman, Ari; Steiner, Günter; Ellmeier, Wilfried

doi:10.1016/j.jaut.2017.09.008

Cited by 41 publications

(36 citation statements)

References 58 publications

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“…In contrast to HDAC1-2 cDKO CD4 + T cells (14), "adding" 1 Hdac2 allele back to HDAC1/HDAC2-deficient CD4 + T cells (HDAC1 cKO -HDAC2 HET ) led to a similar proliferation and survival upon activation in vitro as observed for activated WT CD4 + T cells (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.133393DS1). As previously reported (16,17), HDAC1 cKO CD4 + T cells upregulated IFN-γ ( Figure 1C). Moreover, we observed that activated HDAC1 cKO CD4 + T cells also expressed enhanced levels of EOMES, granzyme B, and T-bet in comparison with activated WT CD4 + T cells (Figure 1, C-E), indicating upregulation of several genes characteristic for Th cytotoxicity and CTLs.…”

Section: Resultssupporting

confidence: 89%

“…Together, the transcriptome analysis suggests the induction of a CTL lineage program in HDAC1 cKO -HDAC2 HET CD4 + T cells. Of note, fold change (FC) expression differences of the top 10 most up-and downregulated genes as well as selected Th cytotoxic lineage genes between activated HDAC1 cKO -HDAC2 HET and WT CD4 + T cells were higher compared with FC expression differences between HDAC1 cKO and WT CD4 + T cells (17) (Figure 2E). This indicates an Hdac1 and Hdac2 gene dosagedependent effect on gene expression levels between HDAC1 cKO and HDAC1 cKO -HDAC2 HET CD4 + T cells.…”

Section: Resultsmentioning

confidence: 99%

“…T cell receptor (TCR) triggering together with IFN-γ stimulation leads to activation of STAT1 via JAK1/2 (29,30). In a previous study we demonstrated that HDAC1 is a crucial negative regulator of STAT1 activation in CD4 + T cells, since activated HDAC1-deficient CD4 + T cells display increased levels of phospho-STAT1 (p-STAT1) (17). Intracellular staining also revealed a strong induction of p-STAT1 in HDAC1 cKO -HDAC2 HET CD4 + T cells ( Figure 4B) but not of Stat1 gene expression ( Figure 2C), while STAT5 phosphorylation was not affected (Supplemental Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

“…(E) Heatmap showing fold change (FC) differences of the top 10 up-and downregulated genes (excluding noncoding RNAs) based on log 2 FC as well as of selected CTL genes between activated WT and HDAC1 cKO -HDAC2 HET CD4 + T cells (activated as described in A). The second lane shows FC differences of these genes between activated WT and HDAC1 cKO CD4 + T cells (anti-CD3/anti-CD28 for 3 days, restimulated with anti-CD3 for 12 hours as previously described) (17).…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Preglej¹,

Hamminger²,

Luu³

et al. 2020

JCI Insight

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During the differentiation of naive CD4 + T cells into effector T cells, cell fate decisions into various Th subsets are made, and Th cell lineage-specific gene expression patterns are established and maintained. Epigenetic mechanisms, such as histone and DNA modifications, play a crucial role in these processes. Among these, modification of core histones by reversible lysine acetylation is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs), which are "classically" considered as transcriptional coactivators and corepressors, respectively. However, HDACs are also recruited to active gene loci and might, potentially with HATs, act context dependently as modulators of gene transcription. Moreover, many nonhistone targets have been emerging, and HATs/HDACs function beyond the epigenetic control of gene expression (10-12). To date, 18 members of the HDAC family (many of which are expressed in the T cell lineage) that are grouped into 4 classes have been identified (13). We have recently generated mice with a T cell-specific deletion of the class I histone deacetylases HDAC1 and HDAC2, which resulted in MHC class II-restricted CD4 + CD8αβ + T cells that, upon activation, initiate the upregulation of a Runx3/ CBFβ-dependent CD8 effector T cell-like program (14,15). This observation indicates that CD4 lineage insight.jci.org

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Preglej¹,

Hamminger²,

Luu³

et al. 2020

JCI Insight

Self Cite

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“…To deplete the Tregs, mice were treated with 200 µg anti-mouse CD25 mAb (BioXcell, West Lebanon, NH, USA) intraperitoneal injection in 200 µl PBS at 3 and 1 days before MCAO. The dosage and injection time points were referred to the previous studies (Christensen et al, 2015;Clemente-Casares et al, 2016;Göschl et al, 2018). The CD3+CD4+CD25+FoxP3+ population depletion was >80% (data have not been shown).…”

Section: Regulatory T Cells Depletionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

Chen

Chencheng

Liu

et al. 2020

Front. Cell. Neurosci.

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Regulatory T cells (Tregs) play an anti-inflammatory effect to protect against ischemic stroke. Plasmacytoid dendritic cells (pDCs) can induce regulatory T cells tolerance in sterile-inflammation conditions. However, whether and how pDCs-mediated Tregs response play a part in the pathology of ischemic stroke remains unclear. In this study, we showed that pDCs were increased in the brain of middle cerebral artery occlusion (MCAO) mice. Depletion of pDCs with 120G8 exacerbated MCAO-induced brain injury, peripheral pro-inflammation response and decreased the systemic Tregs in mice. Furthermore, the data of mixed lymphocyte reaction (MLR) in vitro demonstrate that splenic pDCs from MCAO mice can significantly promote Tregs proliferation, accompanying with the increased expression of indoleamine 2,3-dioxygenase 1 (IDO1) on pDCs. Taken together, the findings here suggested that under the pathologic state of stroke, pDCs protect against MCAO-induced brain injury by priming Tregs, illustrating that pDCs represented as a therapeutic target for the prevention of ischemic brain injury.

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Epigenetics in Multiple Sclerosis

Chan

2020

Advances in Experimental Medicine and Biology

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A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis

Cited by 41 publications

References 58 publications

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

Epigenetics in Multiple Sclerosis

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