Research & Training

Research

Our long-term research interest is to characterize molecular mechanisms that regulate the development and function of T cells. In previous studies we characterized in detail the transcriptional control of the Cd8 gene expression and demonstrated that an active state of Cd8a and Cd8b gene expression is epigenetically maintained during the development of DP thymocytes. We further identified that the transcription factor MAZR is an important regulator of CD8 expression as well as of CD4/CD8 lineage development. In ongoing studies we aim to understand transcriptional networks that control peripheral T cell differentiation/function. Moreover, we are interested in elucidating how histone deacetylases regulate T cell function and study whether HDACs are promising targets for T cell-mediated diseases.

During the last years our research is being supported by:

• Austrian Science Fund (FWF), stand alone project P23641
• Austrian Science Fund (FWF), stand alone project P26193
• Austrian Science Fund (FWF), stand alone project P29790
• FWF/MedUni Wien Doktoratskolleg "Inflammation and Immunity" (W1212)
• Horizon 2020, Marie Sklodowska Curie Innovative Training Network "ENLIGHT-TEN"
• Vienna Science and Technology Fund (WWTF), Life Sciences Call 2009: Project: Epigenetic Regulation of T Cell Development and Function (LS09-031)
• Austrian Science Fund (FWF), stand alone project P23669, awared to Shinya Sakaguchi
• Austrian Science Fund (FWF), stand alone project P27747, awared to Shinya Sakaguchi
• Austrian Science Fund (FWF), stand alone project P24265, awared to Nicole Boucheron
• Austrian Science Fund (FWF), stand alone project P30885, awared to Nicole Boucheron



The role of histone deacetylases in the control of T cell-mediated immunity

Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators during development and differentiation by mediating dynamic changes in the acetylation of histones at lysine residues. In T cells, reversible changes in histone acetylation patterns have been shown to accompany many important processes ranging from VDJ recombination during T cell development to the induction of cytokine expression during Th1/Th2 effector differentiation. Further, in recent years many non-histone targets were identified and reversible lysine acetylation affects protein-protein and protein-DNA interactions, protein stability, enzymatic activity, intracellular localization and is also linked to metabolism. This demonstrates that lysine acetylation is an important post-translational modification likely to be comparable with protein phosphorylation. Eighteen HDACs have been identified in mammalian organisms, however dissecting individual roles for each member of the HDAC family in specific cell lineages and tissues remains a major scientific challenge. In a close collaboration with the research group of Christian Seiser (MedUni Wien) we are analyzing the role of HDAC1, HDAC2 and other members of the HDAC family in T cells and T cell-mediated immune diseases.

Recent results:

A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis. (Göschl L et al., 2017; Journal of Autoimmunity, pii: S0896-8411(17)30595-4. doi: 10.1016/j.jaut.2017.09.008. PubMed link)

CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. (Boucheron, Tschismarov et al., 2014, Nature Immunology, doi: 10.1038/ni.2864, PubMed link)

HDAC1 controls CD8+ T cell homeostasis and antiviral response. (Tschismarov et al., 2014, PLoS One, 9(10):e110576. doi: 10.1371/journal.pone.0110576. PubMed link)

Conditional deletion of HDAC1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. (Grausenburger, R et al. 2010, Journal of Immunology, 185(6): 3489-97, PubMed link)



Molecular analysis of the zinc finger transcription factor MAZR

In our previous studies we identified that the BTB domain-containing zinc finger protein MAZR is an important transcriptional regulator of CD8 expression (Bilic et al., 2006, Nat Immunol) and further demonstrated that MAZR is part of the transcription factor network regulating CD4/CD8 cell fate choice of DP thymocytes (Sakaguchi et al., 2010, Nat Immunol; Sakaguchi et al., J Immunol, 2015). Using mice with a conditional deletion of MAZR in the T cell lineage we are focusing in ongoing studies on the further characterization of MAZR function in CD4+ and CD8+ T cells and in other cells of the hematopoietic system.

Recent results:

MAZR and Runx Factors Synergistically Repress ThPOK during CD8+ T Cell Lineage Development. (Sakaguchi, S., D. Hainberger, C. Tizian, H. Tanaka, T. Okuda, I. Taniuchi, and W. Ellmeier. 2015. J Immunol. 195(6):2879-87. PubMed link)

The transcription factor MAZR preferentially acts as a transcriptional repressor in mast cells and plays a minor role in the regulation of effector functions in response to FceRI stimulation. (Abramova et al., 2013, PLoS One. 8(10):e77677. doi: 10.1371, PubMed link)

The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes. (Sakaguchi et al., 2010, Nat Immunol. 11(5):442-8, PubMed link)



The role of NCOR1 in T cells

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 only poorly understood. In collaboration with Johan Auwerx (University of Lausanne) we are investigating NCOR1 function in T cells.

Recent results:

The corepressor NCOR1 regulates the survival of single-positive thymocytes. (Müller et al, 2017, Scientific Reports 7, Article number 15928, doi:10.1038/s41598-017-15918-0, PubMed link)



Regulation of Cd8 gene expression

Our laboratory is studying the regulation of CD8 coreceptor expression, a key molecule in the immune system for the development of the cytotoxic T cell lineage. CD8 coreceptor expression is tightly regulated during thymocyte development by the activity of at least five 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. We revisited the Cd8ab gene complex with bioinformatics and transgenic reporter gene expression approaches to search for additional Cd8 cis-regulatory elements. This led to the identification of an evolutionary conserved region (ECR-4) that, in transgenic reporter gene expression assays, directed expression preferentially in CD44hiCD62L+ CD8+ T cells including innate-like CD8+ T cells. ECR-4, designated as Cd8 enhancer E8VI, was bound by Runx/CBFβ complexes and Bcl11b, indicating that E8VI is part of the cis-regulatory network that recruits transcription factors to the Cd8ab gene complex in CD8+ T cells. Transgenic reporter expression ceased upon activation, indicating that E8VI is not sufficient to maintain expression in activated CD8+ T cells. Finally, E8VI directed transgene expression also in CD8αα+ dendritic cells but not in CD8αα-expressing IELs. Taken together, we have identified a novel Cd8 enhancer that directs expression in CD44hiCD62L+ CD8+ T cells including innate-like CD8+ T cells and in CD8αα+ DCs and thus our data provide further insight into the cis-regulatory networks that control CD8 expression.

Recent results:

A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8αα+ dendritic cells. (Sakaguchi et al, 2015, J Leukoc Biol. 97(4):635-44, PubMed link)

Cd8 enhancer E8I and Runx factors regulate Cd8a expression in activated CD8+ T cells. (Hassan, Sakaguchi et al., 2011, PNAS. 108(45):18330-5, PubMed link)


Training and Teaching

PhD program "Immunology"

I am the program director of the N094 MedUni Wien international PhD program "Immunology". The objective of the PhD Program Immunology is to provide to students excellent training opportunities in the field of immunology. This will be achieved by offering students the opportunity to work with faculty members on cutting-edge research projects in stimulating research environments. Furthermore, students will obtain an in-depth education and training on various immunological topics to obtain a broad knowledge in the field of immunology. This should help to prepare the students for a successful scientific career within academia and/or life science industry. There are currently more than 70 PhD students enrolled in this program.

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PhD program "Inflammation & Immunity"

My laboratory is also participating in the Doctoral program ("Doktoratskolleg") "Inflammation and Immunity" (IAI), which is co-funded by the Austrian Science Fund (FWF) and the Medical University of Vienna. IAI is an international PhD and MD/PhD Program focusing on Inflammation and Immunity that integrates basic, applied and clinical sciences to provide comprehensive and cutting-edge research training.

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Lectures and Seminars

I am also teaching in the above mentioned PhD programs and are organizing/participating a variety of PhD student seminars and journal clubs.

• Journal Club "Hot topics in Immunology"
• Journal Club "Hot topics in Microbiome Research"
• SE Dissertantenseminar: Molekulare Grundlagen der Abwehrzellentwicklung und -funktion.
• Basislecture Immunology
• Journal Club and Progress Report


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