T regulatory cells (Tregs), a subset of CD4+ T cells (currently known as CD4+CD25+FOXP3+ T cells or immune suppressor cells), are key players in maintaining tolerance and homeostasis of tissues and the immune system. Treg dysregulation critically contributes to various pathologic conditions such as autoimmune diseases, allergic diseases, infectious diseases, cancer, neurodegenerative diseases and metabolic inflammation. In many of these common chronic diseases, the fine-tuned Treg suppressing system is out of balance. It is essential to understand the precise molecular mechanisms underlying Treg suppressor function both, under homeostatic and disease conditions, in order to re-balance an appropriate Treg function as a major therapeutic strategy for many common chronic diseases. The detailed molecular mechanisms underlying and orchestrating the Treg suppressive function on a systemic and tissue-specific level are still not fully understood. The proposed project will investigate functional gene regulatory and signaling networks of Tregs in the context of several barrier diseases by using various murine and human disease models. For this purpose, we will combine various expertises in Tregs, microbiome, single cell analysis, clinical immunology, deep immune phenotyping and computational network analysis in Luxembourg and connect our activities closely with world-class research teams in Treg and microbiome research at RIKEN-IMS (Yokohama, Japan). The success of the proposed theme-based collaborative project will not only significantly leverage our understanding of Treg gene regulatory and signaling networks in barrier diseases, but also identify novel key regulators and gene regulatory motifs as potential therapeutic targets modulating local Treg activity in these diseases.