The Essential Role of Epithelial IRF1 in Shaping the Intraepithelial Lymphocyte Niche 9184

Abstract Description The transcription factor Interferon Regulatory Factor 1 (IRF1) is a key regulator of immune responses and has been implicated in the development and function of various immune cell populations, including natural killer (NK) cells, innate lymphoid cells (ILCs), and T cells. In this study, we investigated the cell-type specific roles of IRF1 in shaping the intraepithelial lymphocyte (IEL) compartment in the small intestine. Using conditional knockout mouse models, bulk and single-cell RNA sequencing, and flow cytometry, we demonstrate that intestinal epithelial cell (IEC)-specific rather than hematopoietic deletion of Irf1 significantly reduces subsets of innate IEL populations, mirroring the effects seen in complete Irf1 knockout mice. Mechanistically, we identify IRF1 as regulator of butyrophilin-like (Btnl) molecule transcription in IECs, which were previously identified as important for γδ IEL accumulation and maintenance in the gut. Further studies using an apicomplexean infection model further established IRF1 as crucial epithelial regulator of IEL homeostasis in both steady-state and infectious diseases. This study provides new insights into the molecular mechanisms underpinning gut immune regulation and offers potential pathways for therapeutic intervention in diseases involving IEL dysfunction. Funding Sources Supported by the german research foundation (TRR241, A03) Topic Categories Mucosal and Regional Immunology (MUC)