Past Research Groups
The immune system has evolved to fight pathogens while remaining tolerant to self and harmless antigens. The need for simultaneous immune vigilance and tolerance is particularly evident in the intestine, which is confronted to antigens coming not only from pathogens, but also from food and harmless commensals. Since the intestine is the largest barrier surface of the body with the outside world, it needs to be able to mount quick, efficient immune responses against potential pathogens. However, most of the intestinal antigens come from the food and the commensal flora, which need to be tolerated. Hence, the intestinal immune system combines a high number of inflammatory cells with a strong population of immune regulators that prevent detrimental reactions against harmless antigens. How the balance between inflammation and tolerance is achieved is still not well understood. The group focuses on the induction and maintenance of immune tolerance, especially through the generation and control of CD4+ Foxp3+ regulatory T cells (Treg). Treg are produced in the thymus or the periphery and prevent misdirected immune responses. They are key to avoid autoimmunity and inflammatory responses against the commensal microbiota. We want to dissect the factors that control the activity of antigen-specific Treg, and we are especially interested in the interactions of intestinal epithelial cells with the immune system.
All inheritable chromosome conditions not encoded by the DNA sequence itself are called epigenetic, including gene expression and for most eukaryotes also centromere and telomere identity. The epigenetic transmission of these states through many cell generations is highly relevant for proper genome regulation and when perturbed can lead to genome instability and cellular malfunction. Centromeres are found at the primary constriction of chromosomes in mitosis where they remain connected before cell division. This structure is essential for an equivalent chromosomes segregation to the daughter cells. Using the fruit fly Drosophila melanogaster as a model organism my lab is particularly interested in the epigenetic regulation of centromere identity with a focus on neocentromere formation in flies and human tissue culture. We are further interested in the nuclear organization of centromeres.
Our research group studies the molecular mechanisms which regulate gene expression, using the NF-kB family of transcription factors as a model system. A major focus is to understand how the activities of transcription factors can be controlled in promoter-specific and cell type-specific fashion. The NF-kB family of transcription factors is crucial for the expression of multiple genes involved in cell survival, proliferation, differentiation and inflammation. The NF-kB pathway is broadly active in multiple cell types, yet many NF-kB target genes show a tightly-regulated pattern of expression, with stimulus-dependent activation restricted to a particular biological setting. To investigate the molecular mechanisms underlying this, we focus on differences in the chromatin structure of target promoters and enhancers, and on co-factors which can regulate the recruitment and activity of NF-kB in specific cell-types.
The aim of our research group is to obtain a global understanding of the signalling pathways that regulate the proliferation and differentiation of B cells. B cells play a key role in adaptive immune response and enable the body to attack pathogens highly efficient and persistent. They bind pathogenic substances at the B cell antigen receptor (BCR). Signals emanating from the BCR or its precursor (pre-BCR) lead to changes in gene expression and determine the fate of developing B cells. Defects in the signal transduction of B cells result in immunodeficiency, autoimmunity or leukaemia. Studying signal transduction in B cell development allows multiple interactions and interdisciplinary collaborations with research groups in both basic science and in the clinic.
The aim of our research group is to understand the biology of functional RNAs in the hematopoietic-immune system. We are focusing on the role of microRNAs in the mammalian hematopoietic-immune system. MicroRNAs are a class of non-coding RNAs binding to the complementary mRNAs and regulate their expression. They are found in animals, plants and viruses with their sequences conserved even among relatively distant species. Various reports have shown the involvement of microRNAs in a broad range of physiological events such as development, differentiation, proliferation, morphogenesis, apoptosis and metabolism. Studying the biology of microRNA in the immune system may directly contribute to understanding the molecular mechanism of immune system integrity. Furthermore, the knowledge of microRNA in immunology would provide clues to elucidate the molecular pathogenesis of infection and immune diseases such as autoimmune and inflammatory diseases.
Classically the main function of the immune system was seen in the defence to pathogenic microorganisms. Now, it is presumed that the immune system is in a constant dialogue with the environment, i.e. with the microbial world and its products at the boundary layer between –defending – organism and outside world. This dialogue is necessary to maintain an ecosystem that allows survival of beneficial microorganisms, but the disposal of deleterious ones. The difference between beneficial and deleterious is most likely not absolute, but rather sliding, and therefore, the recognition strategies of the host is not tailored on pathogens only. Although the immune system most likely evolved at the demarcation line between in and out, immune processes at this line are still a poorly studied part of the immune system. For understanding the immune system, it may actually be the most important one.
One of the major goals of post-genomic biology is to understand the molecular basis and physiological role of covalent protein modifications. We are using histones and the "histone code" as models to study multi-site protein modifications. Our aim is to identify new modifications, to decipher how these modifications are epigenetically inherited and how they can regulate gene expression and chromatin structure. The best studied examples for multi-site protein modifications are currently histone proteins. The complexity and diversity of histone (and other chromatin-associated) modifications add largely to the capacity of the genome to store and process information. We are currently only beginning to understand the many implications of this epigenetic information for biology and disease. Whilst it is still under discussion if histone modifications form a true "code", it has now been established that changes of histone modifications and of protein complexes binding to specific modifications are involved in the regulation of most - if not all - genes in eukaryotic cells. Therefore the significance of studying chromatin modifications extends far beyond the field of chromatin research, because changes in the modification pattern are likely to affect all biological processes.
Transcriptional regulation of blood cell development. The decision to initiate transcription of a gene is the key control point regulatingits expression during development and in response to physiological and environmental stimuli. Understanding the mechanisms of gene expressionhas important implications in understanding development, cellular transformation and many other cellular processes. The focus of my laboratory is to study transcriptional regulation of blood cell development (hematopoiesis) in the mouse. In particular, we want to gain further insights in the physiological significance and function of coactivator and corepressor complexes.
The major interests of the laboratory are the elucidation of the mechanisms underlying the biological activity of bacterial endotoxin (LPS) and other bacterial components, the role of these components in the microbial recognition by the innate immune system and the conditions under which the activity of such components can be altered. Of particular interest is the infection induced LPS hypersensitivity and its role in the innate immune response and defense against intruding pathogens. Sensitivity to LPS is determined by a locus on mouse chromosome 4, designated the lps gene. Mutations of this gene result in unresponsiveness to the lethal and other biological effects of LPS. The identification of the lps gene and its product, with participation of our group, end of 1998, as toll-like receptor 4 (TLR4) brought the breakthrough into a new era for the field of endotoxin research and of microbial products generally. Since the discovery of TLR4, ten different TLR's acting as signaling receptors for microbial components have been identified. This enabled further the study of signaling pathways involved in the activation of cells of the innate immune system.
Our interest are the molecular mechanisms of the activation of T lymphocytes by pathogens. We develop new biochemical techniques for the identification and analysis of multi-protein complexes on a large scale (quantitative proteomics, systems biology). The methods are used to define the protein complexes that change in time and space within the signaling cascades of the antigen TCR. We have determined the TCR stoichiometry, by showing that complexes of different sizes co-exist on the cell membrane. Interestingly, they play different roles in T cell activation. We have detected a conformational change at the TCR induced by ligand-binding that is – together with TCR clustering – required for T cell activation. Our new „permissive geometry model“ of TCR triggering unifies so far irreconcilable findings as crystallographic data of the TCR subunits, studies on the geometry of the ligand (MHC peptide), the presence of multimeric TCR on the cell surface and the role of self-peptide MHC in T cell activation. Blocking the effectors of the conformational change, allowed us to inhibit T cell activation. Thus, auto-immune diseases could be treated by this mechanism. Lastly, we work on the human CD3gamma-deficiency. We have developed a humanized CD3gamma-deficient mouse strain, that shows the same defects as the human patients, and is now used to study this disease in detail.