Cell type-specific functions of the nuclear receptor RORgt

The nuclear hormone receptor RORt is expressed by select subsets of innate and adaptive lymphocytes and antigen-presenting cells and acts as an essential regulator of thymopoiesis, secondary lymphoid tissue development, type 3 immune responses to extracellular bacteria and fungi, and immunological tolerance towards commensal microbes and dietary antigens. RORt-expressing immune cells are key players in inflammatory and autoimmune diseases such as psoriasis, arthritis, inflammatory bowel disease, and colorectal cancer. As a ligand- dependent transcription factor (TF), RORt is a possible therapeutic target; however, due to its essential functions across multiple different cell types, RORt inhibitors have many unintended side-effects. It is still unclear how a single TF can support such a broad variety of seemingly distinct cell types and physiological processes. Understanding how these functions arise on a molecular level may yield new therapeutic opportunities for the treatment of RORt- dependent inflammatory diseases. This project aims to define the direct gene regulatory targets of RORt across different immune cell types in vivo and dissect the molecular underpinnings of its cell type-specific activity. To address these questions, we have generated and validated a genetically modified mouse model that leverages the auxin-inducible degron (AID) system to enable rapid, chemically- induced degradation of RORt protein.