Histone deacetylases as regulators of T-cell-mediated immunity

The immune system is based on a lively exchange of information between the cells, allowing for a coordinated response to combat germs or pathologically modified cells. One group of immune cells that exert important functions in the coordination and fine-tuning of immune responses is formed by T helper (Th) cells. Th cell functions have to be tightly controlled, since dysregulation or inborn errors can lead to immune diseases that are caused by Th cells such as autoimmunity or allergy. One way to regulate Th cells is by regulating how easily DNA information contained in the cells is read. This is often regulated by so-called "epigenetic" processes (i.e. via the degree of DNA packaging") that determine how accessible DNA information is for reading. Special enzymes, the family of his- tone deacetylases (HDACs), play an important role in these processes. In total there are 18 different HDACs and they determine the tightness of DNA packaging". In addition to this, HDACs can also remove small chemical modifications (so-called acetylation) from cellular proteins and thereby reg- ulate the activity of these proteins. The medical importance of HDACs is demonstrated by the fact that broad-spectrum HDAC molecule inhibitors are successfully used for the treatment of patients with certain types of cancer, and these inhibitors directly attack the tumor. The clinical use of these broad-spectrum HDAC inhibitors is limited by the side effects, which underlines the unmet need for more specific HDAC inhibitors. Many preclinical studies using animal models suggest that HDAC inhibitors could also be effective in immune system diseases, like autoimmunity. Despite the fact that T-cells play a crucial role in defining the outcome of immune responses (also against cancer) the exact role of HDACs in T-cells remains poorly understood. HDACs specifically opens/closes certain DNA sections but how is this regulated? Which proteins do they modify in Th cells and how does this change the function of the modified protein? What happens to Th cells if individual HDAC members are inhibited? Are HDACs wrongly regulated in patients with autoimmune diseases? An- swering these questions is important and might pave the way for the application of HDAC inhibitors that target individual HDAC members and that might have less side-effects. In order to address these and many more essential questions and to explore the potential therapeutic benefit of HDAC inhibition, we have formed an interdisciplinary and multi-institutional research network. Our overall aim is to obtain a novel and unprecedented integrated view of HDAC-mediated regulation of Th cells, about the specific functions of individual HDAC family members in Th cells and their im- portance as biomarkers and therapeutic targets in human disease. This is essential to progress to- wards one of the long-term goals of research in this field, which is to exploit HDACs as targets for effective therapeutic strategies to combat immune-mediated and infectious diseases.