Modulation of human gamma/delta T-cell activation and phenotype by histone deacetylase inhibitors

Bhat, Jaydeep; Oberg, Hans‐Heinrich; Kabelitz, Dieter

doi:10.1016/j.cellimm.2015.01.019

Cited by 14 publications

(16 citation statements)

References 40 publications

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“…The sublethal concentration of VPA (5 mM), previously shown to modulate cell surface marker expression on surviving γδ T-cells [ 15 ], induced IL-4δ 13 and IL-4Rα as shown in a representative dot plot in Figure 2A , but no significant IFN-γ expression in Vδ2 T-cells. Results of 3 experiments are summarized in Figure 2B .…”

Section: Resultsmentioning

confidence: 89%

“…We have previously reported that VPA treatment at “toxic” concentration (5 mM) results in selective survival of αβ T-cells over γδ T-cells. Also, treatment of human γδ T-cells with VPA-induced genome-wide histone H3 acetylation and the differential modulation of a restricted set of surface markers only on surviving γδ T-cells in comparison to αβ T-cells [ 15 ]. These findings led us to further investigate the molecular consequences of VPA treatment on short-term expanded human γδ T-cells.…”

Section: Introductionmentioning

confidence: 99%

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Expression of non-secreted IL-4 is associated with HDAC inhibitor-induced cell death, histone acetylation and c-Jun regulation in human gamma/delta T-cells

et al. 2016

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Previously, the expression of a non-secreted IL-4 variant (IL-4δ13) has been described in association with apoptosis and age-dependent Th2 T-cell polarization. Signaling pathways involved in this process have so far not been studied. Here we report the induction of IL-4δ13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ13 was associated with increased cytoplasmic IL-4Rα and decreased IL-4 expression, while mRNA for mature IL-4 was concomitantly down-regulated. Importantly, only the simultaneous combination of apoptosis and necroptosis inhibitors prevented IL-4δ13 expression and completely abrogated VPA-induced global histone H3K9 acetylation mark. Further, our work reveals a novel involvement of transcription factor c-Jun in the signaling network of IL-4, HDAC1, caspase-3 and mixed lineage kinase domain-like protein (MLKL). This study provides novel insights into the effects of epigenetic modulator VPA on human γδ T-cell differentiation.

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Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Expression of non-secreted IL-4 is associated with HDAC inhibitor-induced cell death, histone acetylation and c-Jun regulation in human gamma/delta T-cells

et al. 2016

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“…When comparing human peripheral blood αβ and γδ T cells, we observed substantial differences in the modulation of some surface markers by VPA. Cell surface antigens which were substantially more affected in γδ T cells included CD86, CD54 and NKG2D . We also found that VPA induced the expression of a non‐secreted isoform of IL‐4 (IL‐4 δ 13) in γδ T cells which was linked to histone H3 acetylation and regulation of the c‐Jun transcription factor network .…”

Section: Epigenetic Drugsmentioning

confidence: 63%

Stochastics of Cellular Differentiation Explained by Epigenetics: The Case of T‐Cell Differentiation and Functional Plasticity

et al. 2017

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Epigenetic marks including histone modifications and DNA methylation are associated with the regulation of gene expression and activity. In addition, an increasing number of non-coding RNAs with regulatory activity on gene expression have been identified. Alongside, technological advancements allow for the analysis of these mechanisms with high resolution up to the single-cell level. For instance, the assay for transposase-accessible chromatin using sequencing (ATAC-seq) simultaneously probes for chromatin accessibility and nucleosome positioning. Thus, it provides information on two levels of epigenetic regulation. Development and differentiation of T cells into functional subset cells including memory T cells are dynamic processes driven by environmental signals. Here, we briefly review the current knowledge of how epigenetic regulation contributes to subset specification, differentiation and memory development in T cells. Specifically, we focus on epigenetic mechanisms differentially active in the two distinct T cell populations expressing ab or cd T cell receptors. We also discuss examples of epigenetic alterations of T cells in autoimmune diseases. DNA methylation and histone acetylation are subject to modification by several classes of 'epigenetic modifiers', some of which are in clinical use or in preclinical development. Therefore, we address the impact of some epigenetic modifiers on T-cell activation and differentiation, and discuss possible synergies with T cellbased immunotherapeutic strategies.

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“…The study does not explain the direct effect of HDAC inhibitors on γδ T cells. Earlier study by Kabelitz et al reported that HDAC inhibitor VPA induces differential modulation of cell surface markers on γδ T cells compared to αβ T cells ( 67 ). Although the study shows the direct effect of VPA on γδ T cells, the functional responses of γδ T cells were not investigated in detail.…”

Section: Discussionmentioning

confidence: 99%

Checkpoint Blockade Rescues the Repressive Effect of Histone Deacetylases Inhibitors on γδ T Cell Function

2018

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Histone deacetylases (HDAC) are one of the key epigenetic modifiers that control chromatin accessibility and gene expression. Their role in tumorigenesis is well established and HDAC inhibitors have emerged as an effective treatment modality. HDAC inhibitors have been investigated for their specific antitumor activities and also clinically evaluated in treatment of various malignancies. In the present study, we have investigated the effect of HDAC inhibitors on the effector functions of human γδ T cells. HDAC inhibitors inhibit the antigen-specific proliferative response of γδ T cells and cell cycle progression. In antigen-activated γδ T cells, the expression of transcription factors (Eomes and Tbet) and effector molecules (perforin and granzyme B) were decreased upon treatment with HDAC inhibitors. Treatment with HDAC inhibitors attenuated the antitumor cytotoxic potential of γδ T cells, which correlated with the enhanced expression of immune checkpoints programmed death-1 (PD-1) and programmed death ligand-1 in γδ T cells. Interestingly, PD-1 blockade improves the antitumor effector functions of HDAC inhibitor-treated γδ T cells, which is reflected in the increased expression of Granzyme B and Lamp-1. This study provides a rationale for designing HDAC inhibitor and immune check point blockade as a combinatorial treatment modality for cancer.

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Modulation of human gamma/delta T-cell activation and phenotype by histone deacetylase inhibitors

Cited by 14 publications

References 40 publications

Expression of non-secreted IL-4 is associated with HDAC inhibitor-induced cell death, histone acetylation and c-Jun regulation in human gamma/delta T-cells

Expression of non-secreted IL-4 is associated with HDAC inhibitor-induced cell death, histone acetylation and c-Jun regulation in human gamma/delta T-cells

Stochastics of Cellular Differentiation Explained by Epigenetics: The Case of T‐Cell Differentiation and Functional Plasticity

Checkpoint Blockade Rescues the Repressive Effect of Histone Deacetylases Inhibitors on γδ T Cell Function

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