Assessment of NDRG4, MXI1 and BTG1 in tTreg

The human immune system is regulated by a multitude of modulatory processes which ensure that reactions against pathogens such as bacteria, viruses, fungi and cancer cells can be mounted, while body tissues are not affected. In this context, so-called regulatory T-cells (Treg) are important mediators. Indeed, deficiencies in Treg function can be observed in several diseases, which are caused by aberrant reactions of the immune system (e.g. allergies and autoimmune diseases such as rheumatoid arthritis and type I diabetes). Treg differ from other immune cells by their specific gene expression profile, which governs their unique functions. To the date, this genetic signature has not been fully explored. In the project Assessment of NDRG4, MXI1 and BTG-1 in thymus-derived regulatory T-cells, supervised by Klaus Schmetterer, MD, PhD (Department of Laboratory Medicine, Medical University of Vienna), the role of the three genes NDRG4, MXI1 and BTG1, which were recently discovered as Treg-associated genes, will be further assessed. To that end, these genes will be specifically activated or deactivated by genetic methods and the effects of this manipulation on immune cell function will be evaluated. Novel insights about the function of these three genes in Treg will be gained from these experiments. This could lead to the development of new approaches for the manipulation of Treg in the therapy of allergies and autoimmune diseases. Furthermore, these studies could also provide information whether one or all three genes can be used as diagnostic markers for these diseases.

The reactions of the immune system are governed by diverse mechanisms, which guarantee a ordered onset and termination of immune responses. A specialized cell subset, so called regulatory T-cells (Treg) play a key role in the non-reactivity and termination of immune system components and thereby inhibit overreactions. Aberrant Treg responses can among others lead to autoimmune diseases (e.g. Multiple Sclerosis). In this project, the team around Klaus Schmetterer, Department of Laboratory Medicine, Medical University of Vienna, aimed to unravel novel molecular mechanisms which govern the function of Treg. In this regard, it could be shown that the activity of Treg is completely independent of a key signaling pathway (the so called NF-kB pathway), which to the day has not been described. This finding is especially surprising, since virtually all immune cells rely on this pathway in their activation. Furthermore, a new interaction between cellular metabolism of Treg and factors, which regulate gene expression, could be unveiled. In this context, the role of the protein SOX4 was investigated. SOX4 is a so called transcription factor and regulates specific gene expression patterns. The role of SOX4 in the immune system has not been addressed so far. Additionally, it could be shown that the activity of the SOX4 protein is regulated by processes of cellular metabolism, e.g. autophagy (the "cellular garbage disposal system"). These studies could thus define completely new mechanisms in the regulation of the immune system. In conclusion these studies could provide the basis for a new and enlarged understanding of immune processes. This could lead to novel therapeutic strategies for disease with an immune component (e.g. autoimmune diseases, allergies, organ rejection).