Projects

SFB-F70 HIT Projects:

P01 - Wilfried ELLMEIER: SFB administration and platform coordination.

This project part comprises the scientific and administrative organization of the SFB. A central and essential task of the SFB administration project is, together with the appointed platform coordinators, also the coordination of the research platforms. Next generation sequencing and mass spectrometry experiments will be centrally coordinated, which will also include the standardization and harmonization of sample preparation in order to obtain high-quality NGS and proteomic datasets. These datasets will then be analyzed using the bioinformatics and data integration platform. P01 constitutes the central coordination and interaction hub of the SFB network.
 

P02 – Christoph BOCK: Systems-level analysis of CD4+ T-cell plasticity in response to pharmaceutical and genetic HDAC inhibition

This project part pursues comprehensive and functional analysis of CAR T-cells in response to genetic perturbation of HDAC family members, pursuing potential roles of HDACs in cell-based therapies. HDAC enzymes are key regulators of chromatin that have been implicated in multiple aspects of T-cell development and function. An important role in CAR T-cells is plausible and likely but has not been systematically investigated. In P02, we will take a systems immunology approach to test the hypothesis that HDAC-mediated epigenetic mechanisms play important regulatory roles in CAR T-cell therapy.

P03 – Michael BONELLI: HDACs as targets in systemic autoimmune disease patients.

This project focuses on the potential role of HDACi as a new treatment strategy for Rheumatoid arthritis (RA), focusing both on human patient samples as well as on preclinical models for rheumatoid arthritis.

P04 – Nicole BOUCHERON: HDAC-mediated regulation of T helper (Th) subsets in allergic airway inflammation (AAI).

This project addresses the consequences of HDAC deletion on Th cells generated in AAI models and on the transcriptional and translational profile of Th2 cells driving AAI.

We previously showed that deletion of HDAC1 in T-cells leads to enhanced Th2 responses, with an exacerbation of inflammation in an ovalbumine driven murine allergic airway disease model. By combining a house dust mite (HDM) AAI model and IL-13 tdTomato mice, we showed that T-cell-specific deletion of HDAC1 exacerbates allergic disease independently of the model used by unleashing differentiation and inflammatory features of a pTh2 subset. In addition, we established an in vitro differentiation protocol to generate pTh2 which allowed us not only to perform bulk RNA-seq but also mass spectrometry analysis of pTh2 in absence or presence of HDAC1. These experiments unraveled HDAC1-dependent transcriptional and cellular/metabolic pathways which might provide new insights into therapeutic intervention for AAI.

P05 – Wilfried ELLMEIER: HDAC function in T cells beyond histone modifications.

We previously demonstrated that HDAC1-cKO mice are completely resistant to EAE, raising the exciting possibility of using selective HDAC1 inhibition to treat inflammatory and autoimmune diseases. Class I HDACs have non-catalytic scaffolding functions, and it is unknown whether HDAC1 regulates T cells through such scaffolding functions and/or through its catalytic activity. We will test the hypothesis that the inhibition of HDAC1 catalytic activity is indeed sufficient to induce EAE resistance. Furthermore, we will investigate the acetyl-proteome of primary activated CD4⁺ T cells and its cell type specificity in Th lineages. We hypothesize that Th subset-specific acetylation patterns on non-histone target factors regulate Th effector function and that HDAC-dependent changes in the activity of key non-histone targets contribute to EAE resistance in HDAC1-cKO mice.

P06 – Iris GRATZ: HDAC function in peripheral regulatory T cell biology.

HDACs have context- and tissue-specific roles. This is consistent with the hypothesis that T-cells and structural cells of the respective target tissues are in cellular communication, which in turn regulates the function of T-cells as well as the structural cells. Indeed, in the skin, cutaneous CD4⁺ T-cells produce an array of cytokines that act on KCs, Fibs and ECs to induce specialized host defense and tissue repair responses. Dysregulated CD4⁺ T-cell responses also drive inflammatory skin diseases, and their signals to structural cells of the skin contribute to skin barrier dysfunction. In project P06 we will test the hypothesis that HDACs regulate T-cell functions (including Treg suppressive activity), which impacts the phenotypes and functions of structural skin cells and thus subsequent inflammatory episodes.

P07 – Markus HARTL: HDAC-dependent interactomes and acetylomes in T cells.

Our research group has the objective to investigate the potential of HDACs in regulating T-cells by controlling histones and non-histone proteins. To achieve this, we have established a cutting-edge proteomics technology platform that enables us to quantify and map proteomes, acetylomes, phosphorylomes, and HDAC interactomes.

During our research in the first funding period, we have identified a clear need for quantitative proteomics of specific T-cell subpopulations from limited material. Hence, in the second funding period, we are committed to developing a low input proteomics approach that enables us to analyze proteins of specific Th cell types from less than 10.000 cells. By doing so, we aim to enhance our understanding of the complex regulation of T-cell mediated immunity and how it can be modulated through the activity of HDACs.

P10 – Clarissa CAMPBELL : T cell regulation by SCFA and HDACs during intestinal infection.

Gut bacteria produce short chain fatty acids (SCFA) from the fermentation of dietary fibers. Ace-tate, propionate, butyrate and other SCFA shape the differentiation and function of mucosal CD4+ T cells at the steady state by directly affecting cellular metabolism, engaging G-coupled receptors and modulating HDAC activity. Infection with intestinal helminths increases SCFA levels and attenuates the pathophysiology of extra-intestinal inflammatory diseases; however, whether the SCFA-HDAC axis contributes to regulate CD4+ T cells responses in this context remains unknown. We will employ our expertise in mucosal immunology and bacterial metabolism together with the complementary skillset of other groups in the present consortium to address this open question.

P11 – Thomas KRAUSGRUBER: Deciphering HDAC-dependent cellular communication.

Crosstalk between T-cells and structural cells is essential for maintaining tissue homeostasis, but also involved in regulating the response to inflammatory signals. Building on the SFB consortium’s discovery of compromised migration in HDAC1-deficient T-cells and our preliminary data on structural cells, we hypothesize that HDACs are mediators of cell interactions and regulate the interplay of T-cells and structural cells in an organ-specific manner. This will be investigated in P11.

P08 – Karl KUCHLER: HDACs and T cell-mediated antifungal immunity.

We aim to decipher the HDAC-dependent contributions to CD4+ Th subset polarization and immune surveillance in the antifungal inflammatory responses.  First, we dissect the CD4+ Th plasticity and subset recruitment to infected tissues and organs. Second, we delineate the dynamic adaptive – innate crosstalk at barrier tissues. The key questions of P08 thus include how HDAC function affects organ-specific antifungal immunity for three major human fungal pathogens that show distinct organ tropism (C. albicans - kidney, intestine; C. auris – skin; Aspergillus fumigatus – lung). 

P09 – Christian SEISER: Regulation of HDAC complex function in T cells.

We have  demonstrated that catalytically inactive isoforms of HDAC1 and HDAC2 have dominant-negative effects on the activity of HDAC1/HDAC2 co-repressor complexes. We hypothesize that the expression of catalytically inactive HDAC1 and HDAC2 mimics the effect of isoform HDAC inhibitors. In P09, we will test this hypothesis by examining HDAC1/HDAC2 co-repressor complex activity, chromatin accessibility, gene expression and homeostasis in CD4⁺ T cells expressing inactive HDAC1 and/or HDAC2. Further, the catalytic activity of HDAC1 was shown to be modulated by lysine acetylation and sumoylation. We will analyze the effect of these posttranslational modifications on the regulatory function of HDAC1 in CD4⁺ T cells using acetylated HDAC1 as paradigm for a non-histone target of HATs and HDACs.