A New in vitro model to study the regulatory functions of β cells in early stages of type1 diabetes

Type 1 Diabetes (T1D) is an autoimmune disease marked by the selective destruction of pancreatic β cells. Early insulitis involves interactions between immune cells and β cells, but the mechanisms leading to β cell death are not fully understood. This thesis develops an in vitro co-culture model of β cells with CD4+ T cells to mimic early insulitis and study β cell responses. Cytokine profiling confirmed IFNγ presence and other inflammatory cytokines, indicating bidirectional communication. A significant chromatin remodeling and extensive gene expression changes were observed, identifying new regulatory elements responsive to the stimulus, termed Induced (IREs) and Lost (LoREs) Regulatory Elements. Some of the IREs overlap T1D-risk SNPs, variants that might disrupt normal β cell responses to inflammation. CRISPR activation experiments validated the functional impact of IREs on SOCS1 gene expression. The co-culture model provides insights into β cell responses to immune-mediated inflammation and helps identify potential therapeutic targets for T1D treatment.