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The differentiation of T helper cell subsets and their acquisition of effector functions are accompanied by changes in gene expression programmes, which in part are regulated and maintained by epigenetic processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators that function by mediating dynamic changes in the acetylation of histones at lysine residues. In addition, many non-histone proteins are also acetylated, and reversible acetylation affects their functional properties, demonstrating that HDACs mediate effects beyond the epigenetic regulation of gene expression. In this Review, we discuss studies revealing that HDACs are key regulators of CD4+ T cell-mediated immunity in mice and humans and that HDACs are promising targets in T cell-mediated immune diseases. Finally, we discuss unanswered questions and future research directions to promote the concept that isoform-selective HDAC inhibitors might broaden the clinical application of HDAC inhibitors beyond their current use in certain types of cancer.

In Table 1 in the originally published version of this article, the phenotype of Hdac1-cKO CD8+ T cells (3rd row) was incorrectly described. This has been corrected in the HTML and PDF versions of the manuscript.

Lung pathogenic T helper type 2 (pTh2) cells are important in mediating allergic asthma, but fundamental questions remain regarding their heterogeneity and epigenetic regulation. Here we investigate immune regulation in allergic asthma by single-cell RNA sequencing in mice challenged with house dust mite, in the presence and absence of histone deacetylase 1 (HDAC1) function. Our analyses indicate two distinct highly proinflammatory subsets of lung pTh2 cells and pinpoint thymic stromal lymphopoietin (TSLP) and Tumour Necrosis Factor Receptor Superfamily (TNFRSF) members as important drivers to generate pTh2 cells in vitro. Using our in vitro model, we uncover how signalling via TSLP and a TNFRSF member shapes chromatin accessibility at the type 2 cytokine gene loci by modulating HDAC1 repressive function. In summary, we have generated insights into pTh2 cell biology and establish an in vitro model for investigating pTh2 cells that proves useful for discovering molecular mechanisms involved in pTh2-mediated allergic asthma. Pathogenic T helper type 2 cells (pTh2) are involved in allergic asthma and secrete high levels of IL-5 and IL-13. Here, using HDM challenged mice and developing an in vitro pTh2 culture system, the authors investigate the function of epigenetic modifications in pTh2 cells showing that HDAC1 limits the pathogenicity of pTh2 cells and scRNA analysis of these cells indicates two subsets in the lungs.

FOXP3 + regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4 + T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.

White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1’s function during differentiation. These findings underscore PATZ1’s regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development. Adipogenesis is important for white adipose tissue function. Here the authors identify the transcription factor PATZ1 as a regulator of adipogenesis and adipocyte maintenance, and report that adipose-tissue specific loss of PATZ1 leads to reduced fat mass and larger adipocytes in mice.

The differentiation and function of peripheral helper and cytotoxic T cell lineages is coupled with the expression of CD4 and CD8 coreceptor molecules, respectively. This indicates that the control of coreceptor gene expression is closely linked with the regulation of CD4/CD8 lineage decision of DP thymocytes. Research performed during the last two decades revealed comprehensive mechanistic insight into the developmental stage- and subset/lineage-specific regulation of Cd4, Cd8a and Cd8b1 (Cd8) gene expression. These studies provided important insight into transcriptional control mechanisms during T cell development and into the regulation of cis-regulatory networks in general. Moreover, the identification of transcription factors involved in the regulation of CD4 and CD8 significantly advanced the knowledge of the transcription factor network regulating CD4/CD8 cell-fate choice of DP thymocytes. In this review, we provide an overview of the identification and characterization of CD4/CD8 cis-regulatory elements and present recent progress in our understanding of how these cis-regulatory elements control CD4/CD8 expression during T cell development and in peripheral T cells. In addition, we describe the transcription factors implicated in the regulation of coreceptor gene expression and discuss how these factors are integrated into the transcription factor network that regulates CD4/CD8 cell-fate choice of DP thymocytes.

Background Immune cell metabolism governs the outcome of immune responses and contributes to the development of autoimmunity by controlling lymphocyte pathogenic potential. In this study, we evaluated the metabolic profile of myelin-specific murine encephalitogenic T cells, to identify novel therapeutic targets for autoimmune neuroinflammation. Methods We performed metabolomics analysis on actively-proliferating encephalitogenic T cells to study their overall metabolic profile in comparison to resting T cells. Metabolomics, phosphoproteomics, in vitro functional assays, and in vivo studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), were then implemented to evaluate the effect of metabolic targeting on autoreactive T cell pathogenicity. Finally, we confirmed the translational potential of our targeting approach in human pro-inflammatory T helper cell subsets and in T cells from MS patients. Results We found that autoreactive encephalitogenic T cells display an altered coenzyme A (CoA) synthesis pathway, compared to resting T cells. CoA fueling with the CoA precursor pantethine (PTTH) affected essential immune-related processes of myelin-specific T cells, such as cell proliferation, cytokine production, and cell adhesion, both in vitro and in vivo. Accordingly, pre-clinical treatment with PTTH before disease onset inhibited the development of EAE by limiting T cell pro-inflammatory potential in vivo. Importantly, PTTH also significantly ameliorated the disease course when administered after disease onset in a therapeutic setting. Finally, PTTH reduced pro-inflammatory cytokine production by human T helper 1 (Th1) and Th17 cells and by T cells from MS patients, confirming its translational potential. Conclusion Our data demonstrate that CoA fueling with PTTH in pro-inflammatory and autoreactive T cells may represent a novel therapeutic approach for the treatment of autoimmune neuroinflammation.

Dasatinib is a small-molecule kinase inhibitor used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). We have analyzed the kinases targeted by dasatinib by using an unbiased chemical proteomics approach to detect binding proteins directly from lysates of CML cells. Besides Abl and Src kinases, we have identified the Tec kinases Btk and Tec, but not Itk, as major binders of dasatinib. The kinase activity of Btk and Tec, but not of Itk, was inhibited by nanomolar concentrations of dasatinib in vitro and in cultured cells. We identified the gatekeeper residue as the critical determinant of dasatinib susceptibility. Mutation of Thr-474 in Btk to Ile and Thr-442 in Tec to Ile conferred resistance to dasatinib, whereas mutation of the corresponding residue in Itk (Phe-435) to Thr sensitized the otherwise insensitive Itk to dasatinib. The configuration of this residue may be a predictor for dasatinib sensitivity across the kinome. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Furthermore, dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer therapeutic opportunities for inflammatory and immunological disorders.

Histone deacetylases (HDACs) are crucial regulators of cell identity. Ellmeier and colleagues show that HDAC1 and HDAC2 maintain CD4 + T cell lineage integrity by repressing Runx-CBFβ complexes in T H 1 cells but not in T H 2 cells. Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases 1 and 2 (HDAC1 and HDAC2) as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of major histocompatibility complex (MHC) class II–selected CD4 + helper T cells that expressed CD8-lineage genes such as Cd8a and Cd8b1 . HDAC1 and HDAC2–deficient T helper type 0 (T H 0) and T H 1 cells further upregulated CD8-lineage genes and acquired a CD8 + effector T cell program in a manner dependent on Runx-CBFβ complexes, whereas T H 2 cells repressed features of the CD8 + lineage independently of HDAC1 and HDAC2. These results demonstrate that HDAC1 and HDAC2 maintain integrity of the CD4 lineage by repressing Runx-CBFβ complexes that otherwise induce a CD8 + effector T cell–like program in CD4 + T cells.

CD4 + and CD8 + T cells are considered distinct functional lymphocyte subsets. Cheroutre and Mucida and their colleagues show that mature gut-associated CD4 + T cells lose ThPOK expression and reactivate CD8 cytolytic effector programs. TCRαβ thymocytes differentiate into either CD8αβ + cytotoxic T lymphocytes or CD4 + helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II–restricted CD4 + thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4 + T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4 + T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II–restricted CD4 + cytotoxic T lymphocytes.