Epithelial IRF-1 signaling controls intra-epithelial T cell residency and associated protection from IBD

We and others have recently shown that intestinal epithelial cells (IECs) are central players in immune responses during IBD. They can both increase or calm the inflammation by secreting molecules and interacting with immune cells during IBD. Interferons are central modulators of an immune response, and Interferon regulatory factor (IRF)-1 is a non-redundant transcription factor required by all Interferon receptors to function. Mutations in the genes comprising the IRF-1 molecular cascade are also associated with an increased risk of IBD. However, the role of IRF-1 signaling in the epithelial cells has not been explored. Our unpublished preliminary data show that epithelial IRF-1 protects T cells from death in the gut and provokes a helpful immune response from them. These T cells protect from inflammation by limiting the accumulation of an ATP alarmin that triggers a pathogenic sequela that underlies IBD. To understand how IRF-1 provides this protection, we have generated several novel mice, commensal and pathogenic bacterial strains with cutting-edge gene-editing techniques. Therefore, these studies will provide critical insights into the development of IBD and targeted therapeutic strategies for its treatment, including the potential for a novel class of IRF1-agonists and specific cell death inhibitors.