Report
Teaser, summary, work performed and final results
Periodic Reporting for period 3 - REGiREG (Regulating the immune regulators: targeting adaptive immune control)
Teaser
The immune system with its complex interactions of cells and molecules needs a very tight and specific interplay of control elements to ensure the establishment and re-establishment of immune homeostasis after challenges. Regulatory T cells are key-players in this regulatory...
Summary
The immune system with its complex interactions of cells and molecules needs a very tight and specific interplay of control elements to ensure the establishment and re-establishment of immune homeostasis after challenges. Regulatory T cells are key-players in this regulatory network. It is now well accepted that deficiency or dysfunction of regulatory T cells causes various severe immune disorders due to immune hyperactivation. Conversely, an increased number of regulatory T cells in tumor-bearing individuals suppresses efficient anti-tumor immunity and, thereby, is often associated with poor prognosis. Cancer immunology is now one of the most exciting and promising frontiers in cancer research, and recent clinical trials have proven that immunotherapies driving to activate T cells can induce durable responses. In this sense, harnessing the potential of regulatory T cells is one of the most promising new approaches to control immune function and to treat cancer. This proposal has two objectives: 1, the identification and characterization of tissue-resident regulatory T cells to principally understand the unique features of regulatory T cell specialization in tissues and their function in organ-homeostasis, a phenomenon that is hardly understood, but holds great promise for local, tissue-specific immune intervention. 2, to globally target regulatory T cells, including the lymphoid organ regulatory T cell pool, by interfering with their survival and or suppression function. We expect from these studies new basic insights into a fascinating and still arcane aspect of organ-homeostasis as maintained by regulatory T cells, as well as novel inhibitors and candidate molecules that target regulatory T cells at the systemic level, and eventually at a tissue-specific level.
Work performed
Within the first 30 month of the project, we were able to establish several novel tools and technologies to study regulatory T cells within tissues. We established new in vivo model systems and in vitro test systems. We characterized regulatory T cells on a molecular level from different tissues. For examples, we performed epigenetic analysis with a tagmentation-based whole-genome bisulfite sequencing technology, which allowed us to analyze the DNA methylation status of very few Treg cells isolated from tissues. With this technology, we were able to study the epigenetic changes of DNA methylation with the highest possible resolution (single nucleotide and genome-wide). This tagmentation-based whole-genome bisulfite sequencing of tissue and lymphoid T cells revealed more than 11,000 differentially methylated regions. Similarities of the epigenetic landscape led to the identification of a common tissue Treg population, present in many organs and characterized by gain and loss of DNA methylation, including many TH2-specific sites. Furthermore, this newly introduced ST2-expressing population, which we called tisTregST2, was dependent on the transcriptional regulator BATF and could be vigorously expanded by IL-33. Thus, we could show that tissue Treg cells integrate different waves of epigenetic reprogramming which define their tissue-restricted specializations. The corresponding manuscript has been published in Nature Immunology (Delacher M et al. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nature Immunology, 2017;18(10):1160-1172).
Final results
We implemented novel technologies to analyze Treg and conventional T cells from peripheral organs and lymphoid tissues. Those included DNA methylation technologies and open chromatin analysis by ATAC-sequencing. The assay for transposase-accessible chromatin is a technique to study chromatin accessibility. With these whole-genome sequencing technologies, we were able to study the epigenetic landscape and to recognize the permanent underlying molecular programs. Furthermore, we identified additional tissue-resident Treg cell targets for therapeutic intervention.