Imaging mass cytometry reveals early β-cell dysfunction and changes in immune signatures during type 1 diabetes progression in human pancreata

The natural history and pathogenesis of type 1 diabetes, particularly during the autoantibody- positive stages preceding clinical onset, are not well understood, in part, due to limited availability of human pancreatic samples. Here, we studied 88 organ donors, including 28 single autoantibody-positive and 10 multiple autoantibody-positive donors, by imaging mass cytometry. Approximately 10,000 islets and 16 million single-cells were spatially analyzed using 79 antibodies revealing both β-cell states and the islet-immune interface. We identified IAPP loss from β-cells as an indicator of pre-clinical disease. Alterations in Interferon signatures and downregulation across lineage and functional markers, including markers of endoplasmic reticulum stress, were characteristic of recent-onset disease. Further, in single autoantibody- positive donors, we identified pro-inflammatory myeloid cells and PD1 ⁺ memory CD4 ⁺ T cells, and in multiple autoantibody-positive samples, found islet-specific and exhausted-like ebector CD8 ⁺ T cells. Multiple immune cell subtypes were associated with young age, disease severity and insulitis. This dataset is a major step toward creation of a multi-modal type 1 diabetes disease atlas that will be useful for identifying potential drug targets and association of disease features with clinical co-variates and trial outcomes.