Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells. Disease etiology is dependent on the interplay of multiple heterogeneous cell types in the pancreatic environment; however, technical constraints have thus far impeded our understanding of the initial molecular perturbations that occur during disease progression and a comprehensive identification of the pathogenic cell types in T1D. In particular, it is difficulty to safely biopsy the human pancreas of living donors, and there is significant disease progression and beta cell destruction by the time patients are clinically diagnosed with T1D. To address this, the Human Pancreas Analysis Program (HPAP) collects pancreatic tissues from deceased organ donors diagnosed with T1D and performs comprehensive molecular phenotyping. Using the full spectrum of imaging, genetic, and genomic technologies available through HPAP, we discovered that a subset of pancreatic ductal cells acquires the signature of tolerogenic dendritic cells in an apparent attempt at immune suppression in T1D donors. Single cell RNA-seq revealed a highly significant enrichment of the tolerogenic dendritic cell gene signature in ductal cells of T1D donors, including activation of interferon genes. In addition, via highly multiplexed flow CyTOF, we identified a population of ductal cells expressing dendritic cell proteins that was enriched in pancreata from T1D donors. Finally, we confirmed these results independent of islet culture via analysis of spatial features in pancreatic tissue using imaging mass cytometry. Together, our multi-modal analyses, ranging from transcriptomics to spatial proteomics, suggest that in the setting of disease, ductal cells are transcriptionally similar to tolerogenic ductal cells These results imply a previously unappreciated role of these exocrine cells in modulating immune cell activity in long-term T1D. Disclosure K. H. Kaestner: None. Hpap consortium: n/a. G. Vahedi: None. Funding NIH UC4 DK112217NIH R01CA230800Susan G. Komen CCR185472448 NIH R01HL145754NIH U01DK127768The Burroughs Wellcome FundThe Chan Zuckerberg Initiative, Penn EpigeneticsThe Sloan Foundation
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