Analysis of the epigenetic modifications of T cell subsets

Autoimmune diseases like Rheumatoid Arthritis, Type1 Diabetes or Multiple Sclerosis are still a major cause of morbidity in the industrialized world. The pathogenesis of these diseases is still unresolved. Recent evidence supports the notion that T helper (Th)1 and Th17 cells are among the major drivers of autoimmune diseases. Nevertheless, T cell targeted therapies are still not effective in a large majority of patients. This is likely due to the fact that these compounds act in a non-specific manner. Therefore it has become increasingly necessary to understand differentiation pathways of T cell lineages under pathogenic in vivo conditions in order to develop more targeted therapies. To date, still little is known about the epigenetic modifications that govern effector T cells differentiation. New high-throughput, comprehensive approaches, such as chromatin immunoprecipitation with massive parallel sequencing, allow quantitative, genome-wide analysis of epigenetic modifications, transcription factor binding and RNA expression. These analyses have provided a detailed picture of T cell "lineages", but have also led to the surprising finding of "bivalent" epigenetic marks of master regulator transcription factors. This provides the opportunity for unexpected flexible expression and raises the possibility that T cell lineages could be reprogrammed under certain conditions. Present studies have focused their analysis on in vitro generated murine T cell subsets whereas little is known in regard to the regulation of T cell plasticity in vivo. Therefore the aim of the present study is to analyze epigenetic modifications of effector T cells in order to determine their commitment versus flexibility under in vitro and under pathogenic in vivo conditions. In the first part of this study we plan to analyze the epigenetic modifications of in vitro differentiated Th1 and Th17 cells after several differentiation time-points. Thereby we expect to gain a detailed epigenetic profile of differentially generated effector T cells. In the second part of this study we plan to analyze epigenetic modifications of effector T cells that develop under pathogenic conditions, in an autoimmune and an infectious model. In particular the experimental autoimmune encephalitis model and an infectious model with Helicobacter pylori and Toxoplasma gondii will be used. This will enable comparative analyses of epigenetic modifications of T cells that derive in vitro and under pathogenic in vivo conditions. Thereby we expect to identify changes in the epigenetic signature that occur along their differentiation pathway. This detailed road map of T cell differentiation might ultimately serve to develop strategies for targeted therapies to reprogram pathogenic T cells.