Wilfried Ellmeier

Wilfried Ellmeier
Medical University of Vienna | MedUni Vienna · Institute of Immunology

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138
Publications
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Publications

Publications (138)
Preprint
White adipose tissues (WAT) play a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription fact...
Article
The two major subsets of peripheral T cells are classically divided into the CD4⁺ T helper cells and the cytotoxic CD8⁺ T cell lineage. However, the appearance of some effector CD4⁺ T cell populations displaying cytotoxic activity, in particular during viral infections, has been observed, thus breaking the functional dichotomy of CD4⁺ and CD8⁺ T ly...
Preprint
FOXP3 ⁺ regulatory T cells (Tregs) are key for immune homeostasis. Tregs are a heterogenous population, however mechanisms regulating their transition from naïve to effector Tregs (eTregs) are poorly understood. Here, we reveal a novel role for nuclear receptor corepressor 1 (NCOR1) in effector Tregs (eTregs). NCOR1 represses an effector signature...
Preprint
Objective 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating primary sclerosing cholangitis (PSC), an immune-mediated cholestatic liver disease. Since PSC strongly associates with inflammatory bowel diseases (IBD) driven by T H 17/Treg imbalance, we aimed to explore NorUDCA’s immunomodulatory potential on intestinal...
Article
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T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known...
Article
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Background & Aims 24-NorUrsodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC) where dysregulated T-cells including CD8⁺ T-cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8⁺ T-cell function th...
Article
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CD4⁺ T cell trafficking is a fundamental property of adaptive immunity. In this study, we uncover a novel role for histone deacetylase 1 (HDAC1) in controlling effector CD4⁺ T cell migration, thereby providing mechanistic insight into why a T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis (EAE). HDAC1-def...
Article
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The importance of cellular metabolic adaptation in inducing robust T cell responses is well established. However, the mechanism by which T cells link information regarding nutrient supply to clonal expansion and effector function is still enigmatic. Herein, we report that the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK)...
Article
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The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8+ T cell differentiation. In contrast to the...
Article
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Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell–specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transfo...
Preprint
Background & Aims 24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8 ⁺ T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8 ⁺ T cell effector function thus contributing to its therapeutic...
Chapter
Reversible lysine acetylation of histones is a key epigenetic regulatory process controlling gene expression. Reversible histone acetylation is mediated by two opposing enzyme families: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Moreover, many non-histone targets of HATs and HDACs are known, suggesting a crucial role for ly...
Preprint
Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell popul...
Article
Full-text available
The differentiation of naïve CD4+ T cells into T helper (Th) subsets is key for a functional immune response and has to be tightly controlled by transcriptional and epigenetic processes. However, the function of cofactors that connect gene-specific transcription factors with repressive chromatin-modifying enzymes in Th cells is yet unknown. Here we...
Article
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Protein phosphatase 2A (PP2A) is an important regulator of signal transduction pathways and a tumor suppressor. Phosphorylation of the PP2A catalytic subunit (PP2AC) at tyrosine 307 has been claimed to inactivate PP2A and was examined in more than 180 studies using commercial antibodies, but this modification was never identified using mass spectro...
Article
Full-text available
Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key de...
Article
Full-text available
Forkhead box protein P3+ (FOXP3+) regulatory T cells (Treg cells) play a key role in maintaining tolerance and immune homeostasis. Here, we report that a T cell-specific deletion of the transcription factor MAZR (also known as PATZ1) leads to an increased frequency of Treg cells, while enforced MAZR expression impairs Treg cell differentiation. Fur...
Article
Rheumatoid Arthritis (RA) represents a chronic T cell-mediated inflammatory autoimmune disease. Studies have shown that epigenetic mechanisms contribute to the pathogenesis of RA. Histone deacetylases (HDACs) represent one important group of epigenetic regulators. However, the role of individual HDAC members for the pathogenesis of arthritis is sti...
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Invariant natural killer T (iNKT) cells represent a subgroup of innate-like T cells and play an important role in immune responses against certain pathogens. In addition, they have been linked to autoimmunity and antitumor immunity. iNKT cells consist of several subsets with distinct functions; however, the transcriptional networks controlling iNKT...
Conference Paper
Background Despite enormous efforts to develop new therapeutic strategies for treatment of rheumatoid arthritis (RA), the large number of non responding patients to currently available drugs underlies the unmet need to identify new therapeutic targets. Certain CD4⁺T cell subsets, especially those polarized toward the T helper (Th) subsets Th1 andTh...
Article
Full-text available
CD8 expression in T lymphocytes is tightly regulated by the activity of at least six Cd8 enhancers (E8I-E8VI), however their complex developmental stage-, subset-, and lineage-specific interplays are incompletely understood. Here we analyzed ATAC-seq data on the Immunological Genome Project database and identified a similar developmental regulation...
Article
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Nuclear receptor corepressor 1 (NCOR1) is a transcriptional corepressor that links chromatin‐modifying enzymes with gene‐specific transcription factors. Although identified more than 20 years ago as a corepressor of nuclear receptors, the role of NCOR1 in T cells remained only poorly understood. However, recent studies indicate that the survival of...
Article
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 cha...
Article
Chemokines mold the tumor microenvironment by recruiting distinct immune cell populations, thereby strongly influencing disease progression. Previously, we showed that CXCL5 expression is upregulated in advanced stages of primary melanomas, which correlates with the presence of neutrophils in the tumor. Analysis of neutrophil populations in various...
Article
Full-text available
Nuclear receptor corepressor 1 (NCOR1) is a transcriptional regulator bridging repressive chromatin modifying enzymes with transcription factors. NCOR1 regulates many biological processes, however its role in T cells is not known. Here we show that Cd4-Cre-mediated deletion of NCOR1 (NCOR1 cKOCd4) resulted in a reduction of peripheral T cell number...
Article
Multiple sclerosis (MS) is a human neurodegenerative disease characterized by the invasion of autoreactive T cells from the periphery into the CNS. Application of pan-histone deacetylase inhibitors (HDACi) ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model for MS, suggesting that HDACi might be a potential therapeutic stra...
Article
The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compen...
Article
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How functionally diverse populations of pathogen-specific killer T cells are generated during an immune response remains unclear. Here, we propose that fine-tuning of CD8αβ co-receptor levels via histone acetylation plays a role in lineage fate. We show that lysine acetyltransferase 6A (KAT6A) is responsible for maintaining permissive Cd8 gene tran...
Article
T cells must tightly regulate their metabolic processes to cope with varying bioenergetic demands depending on their state of differentiation. The metabolic sensor AMPK is activated in states of low energy supply and modulates cellular metabolism toward a catabolic state. Although this enzyme is known to be particularly active in regulatory T (Treg...
Article
Full-text available
Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ)...
Article
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Lipid rafts, a distinct class of highly dynamic cell membrane microdomains, are integral to cell homeostasis, differentiation, and signaling. However, their quantitative examination is challenging when working with rare cells, developmentally heterogeneous cell populations, or molecules that only associate weakly with lipid rafts. We present a fast...
Article
Th-inducing Pox virus and zinc finger/Krüppel-like factor (ThPOK) is a key commitment factor for CD4(+) lineage T cells and is essential for the maintenance of CD4 lineage integrity; thus, the expression of ThPOK has to be tightly controlled. In this article, we demonstrate that Myc-associated zinc finger-related factor (MAZR) and Runt-related tran...
Article
CD4(+) helper T cells and CD8(+) cytotoxic T cells form the two major subsets of peripheral T lymphocytes. Helper T cells fulfill crucial roles in the activation and coordination of the immune response, while cytotoxic T cells kill virus-infected or tumor cells. Recent data suggest that the lineage identify of helper T cells is not fixed and that C...
Article
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Tyrosine kinase pathways are known to play an important role in the activation of platelets. In particular, the GPVI and CLEC-2 receptors are known to activate Syk upon tyrosine phosphorylation of an Immune Tyrosine Activation Motif (ITAM) and hemi-ITAM, respectively. However, unlike GPVI, the CLEC-2 receptor contains only one tyrosine motif in the...
Article
Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibito...
Article
CD8 coreceptor expression is dynamically regulated during thymocyte development and is tightly controlled by the activity of at least 5 different cis-regulatory elements. Despite the detailed characterization of the Cd8 loci, the regulation of the complex expression pattern of CD8 cannot be fully explained by the activity of the known Cd8 enhancers...
Article
Full-text available
Author Summary Inflammasomes represent multi-protein complexes and their activation during microbial infections is key in driving hyperinflammation through the maturation and release of IL-1β, as well as by directly inducing several pro-inflammatory cytokines during the host pathogen interaction. Thus, inflammasomes are involved in the induction of...
Article
Full-text available
Reversible lysine acetylation plays an important role in the regulation of T cell responses. HDAC1 has been shown to control peripheral T helper cells, however the role of HDAC1 in CD8+ T cell function remains elusive. By using conditional gene targeting approaches, we show that LckCre-mediated deletion of HDAC1 led to reduced numbers of thymocytes...
Article
The proper regulation of the development and function of peripheral helper and cytotoxic T cell lineages is essential for T cell-mediated adaptive immunity. Progress made during the last 10-15 years led to the identification of several transcription factors and transcription factor networks that control the development and function of T cell subset...
Article
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...
Article
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Mast cells are key players in type I hypersensitivity reactions in humans and mice and their activity has to be tightly controlled. Previous studies implicated the transcription factor MAZR in the regulation of mast cell function. To study the role of MAZR in mast cells, we generated a conditional Mazr allele and crossed Mazr (F/F) mice with the Va...
Article
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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...
Article
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In this study we investigated the role of Bruton's tyrosine kinase (Btk) in the immune response to the Gram-positive intracellular bacterium Listeria monocytogenes (Lm). In response to Lm infection, Btk was activated in bone marrow-derived macrophages (BMMs) and Btk (-/-) BMMs showed enhanced TNF-α, IL-6 and IL-12p40 secretion, while type I interfe...
Data
Schematic drawing showing possible interactions of Btk with Lm-induced innate signaling pathways. Lm induces TLR2 signaling and several intracellular signaling pathways. TLR2 signaling results in MyD88-mediated activation of NF-κB or MAPK pathways, leading to the production of pro-inflammatory cytokines. Lm engulfed in the phagosome can also trigge...
Data
Impaired escape of Lm from phagosomes of Btk−/− BMMs. (A) Wt and Btk−/− BMMs were infected with Lm (LO28, MOI 40) and three hours later cells were fixed, permeabilized and cellular actin was stained with Phalloidin-Alexa (red). Bacteria were stained using an α-Lm antibody and a corresponding secondary antibody (AlexaFluor 488, green). The total num...
Data
Exogenously added cytokines do not influence Lm uptake or escape. Wt BMMs were infected with CFSE-labeled Lm (LO28, MOI 40) in the presence of TNF-α, IL-6 and IL-12 (the cytokine concentrations were in a range measured in the culture supernatants of Btk-deficient cells; TNF-α 14,7 ng/ml, IL-6 21 ng/ml and IL-12 1,5 ng/ml). Three hours later cells w...
Article
Full-text available
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 con...
Article
Full-text available
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...
Article
ABSTRACT Members of the Tec kinase family (Tec, Btk, Itk, Rlk, and Bmx) play an important role during innate and adaptive immune responses, and mutations in Tec family kinases are linked with immunodeficiencies in humans and mice. Three members of the Tec kinase family are expressed in T cells (Tec, Itk, and Rlk), and biochemical and genetic studie...
Article
The helper versus cytotoxic-lineage choice of CD4(+)CD8(+) DP thymocytes correlates with MHC restriction of their T cell receptors and the termination of either CD8 or CD4 coreceptor expression. It has been hypothesized that transcription factors regulating the expression of the Cd4/Cd8 coreceptor genes must play a role in regulating the lineage de...
Article
Full-text available
Cd8a and Cd8b1 coreceptor gene (Cd8) expression is tightly controlled during T-cell development by the activity of five Cd8 enhancers (E8(I)-E8(V)). Here we demonstrate a unique transcriptional program regulating CD8 expression during CD8(+) effector T-cell differentiation. The Cd8 enhancer E8(I) and Runx/core-binding factor-β (CBFβ) complexes were...
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The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec...
Article
Full-text available
Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. L...
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T cells and level of the cytokine interferon-γ (IFN-γ) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-γ and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis. We used...