Cell type-specific functions of the nuclear receptor RORgt

The nuclear hormone receptor ROR<U+F067>t 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. ROR<U+F067>t-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), ROR<U+F067>t is a possible therapeutic target; however, due to its essential functions across multiple different cell types, ROR<U+F067>t 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 ROR<U+F067>t- dependent inflammatory diseases. This project aims to define the direct gene regulatory targets of ROR<U+F067>t 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 ROR<U+F067>t protein.

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