Imaging mass cytometry reveals functional and immunological changes during type 1 diabetes progression in human pancreata.

The pathogenesis of type 1 diabetes, particularly at autoantibody-positive preclinical stages, remains poorly understood, in part due to limited sample availability. Here we show imaging mass cytometry data of pancreas samples from 88 organ donors, including 28 single and 10 multiple autoantibody-positive donors. We imaged 16 million single-cells using 79 antibodies to characterize β-cell states and the islet-immune interface, correcting for relevant covariates. We identified interactions between pro-inflammatory macrophages and exhausted-like (PD1+TIM3+) T cells. These interactions were characteristic of early disease and of insulitic islets, indicating a key role of macrophages in disease development. β-cells showed loss of IAPP in preclinical disease, insulitic interferon signatures and no increase in three measured endoplasmic reticulum stress markers in disease samples relative to control. Multiple immune cell subtypes were associated with young age and insulitis, potentially contributing to greater disease severity in younger patients. Our data present a resource describing early type 1 diabetes progression and reveal potentially clinically actionable features before extensive β-cells loss.