Type 1 diabetes (T1D) is a chronic autoimmune disease caused by the destruction of pancreatic beta cells in the islets of Langerhans. Genome-wide associated studies (GWAS) have implicated several dozen genes in T1D, but few are expressed by or unique to beta cells. We hypothesize that a combination of genetic and environmental factors contributes to immune and exocrine-endocrine crosstalk leading to the loss of beta cell mass. In this multidisciplinary study, we will investigate the relationship between pancreatic tissue types, inflammation, and genotypes to uncover new insights into the initiating events of T1D. We will generate immune cells and pancreatic exocrine and endocrine organoids with induced pluripotent stem (iPS) cells derived from patients with T1D to produce a reproducible platform for our proposed study. Specific Aim 1 will delineate transcriptional and chromatin accessibility changes of pancreatic exocrine and endocrine tissues under inflammation with T1D-risk variants to identify T1D cell type-specific regulatory programs. Specific Aim 2 will determine changes in pancreatic exocrine and endocrine function on immune responses with T1D-risk variants. Specific Aim 3 will establish a microcontact printing co-culture system of pancreatic exocrine and endocrine tissue to investigate tissue interactions in the context of stress with T1D-risk variants. The multi- tissue assemblies will be evaluated with spatial transcriptomics to identify the relationship between tissue cross-talk and transcriptional identity. Successful completion of this study will provide a better understanding of the relationship between pancreatic exocrine and endocrine cells in the context of defined genotypes and environmental factors in the development of T1D. The data and novel co-culture platform generated in this study will benefit the T1D community.