Novel molecular regulators of type I interferon expression and plasmacytoid dendritic cell differentiation
Crucial for the outcome of an infectious disease are the spatiotemporal interactions of cytokine-producing cells on the one hand with the pathogen and on the other hand with the target cells of cytokines - the soluble messengers of the immune system - in the host organism. The Scheu group investigates these cytokine producers of the immune system and their function in the immune defense against viral, bacterial and eukaryotic pathogens and in the development of autoimmune diseases. One focus of our work is on dendritic cells (DCs), the professional antigen-presenting cells, and on the cytokine family of type I interferons. Type I interferons play a key role at the interface between innate and adaptive immune responses in combating viral infections but also in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis. Using sensitive fluorescence reporter models, we visualize type I interferon producers in complex in vivo infection models at the cellular level and thus have direct access to characterize the cellular and molecular biological regulatory mechanisms of their differentiation and effector functions. Here, we use bioinformatic methods in genome-wide multi-omics analyses and have recently been able to identify novel molecular regulators of type I interferon production specifically in plasmacytoid dendritic cells. This DC type in particular has the ability to produce high levels of type I interferon in response to a viral stimulus and thus can be crucial in the early control of viral infections. Furthermore, we are currently investigating the role of these plasmacytoid dendritic cells in the development of sepsis-induced immune dysregulation leading to increased susceptibility to secondary infections after surviving acute sepsis.
With the goal of identifying novel immunomodulatory compounds with concurrent direct anti-tumor and/or anti-pathogenic properties, we are conducting a screen of a natural product library and natural product-derived novel histone deacetylase inhibitors. Several promising candidates that have specific capacity to activate dendritic cells have already been defined. Current work is focused on target finding and defining the underlying molecular mechanisms.
Another research topic concerns the biology of tetraspanins, which are transmembrane proteins that control numerous processes in CNS development and immune defense, among others. Tetraspanin 2 (Tspan2) was originally described in oligodendrocyte progenitor cells, but has remained poorly characterized to date. We are working to elucidate the role of Tspan2 in viral, bacterial, and fungal immune defenses and in CNS autoimmunity with direct relevance to the potential use of Tspan2 and other tetraspanins as therapeutic targets in anti-infective immune responses
Our newly defined molecular regulatory mechanisms and properties of effector cells of the immune system provide an important basis for the new and further development of innovative vaccination and therapy strategies for infectious, but also autoimmune and tumor diseases.
Communication of plasmacytoid dendritic cells and dendritic cell precursors in bone marrow during sepsis-induced immune dysregulation
Immunomodulatory functions of IFNβ-producing microglia in CNS autoimmunity