A surviving beta cell subpopulation enriched in patients with T1D.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic beta cells. While most beta cells are lost, a subset of beta cells persists years and even decades after disease onset. Studying these surviving cells is challenging, and thus how they escape immune killing remains poorly understood. Here, we applied a gene regulatory network inference-based clustering approach on existing islet scRNAseq data from cadaveric donors with T1D, autoantibody positive donors at risk for T1D, and non-diabetic donors to analyze beta cells from patients with established T1D. This approach identified a novel beta cell subtype enriched in T1D donors defined by the activity of several transcription factors which have well-characterized roles in beta cell survival, most notably IRF1. We found increased expression of immunomodulatory genes (e.g. SOCS1/3, HLA-E) as well as decreased expression of autoantigens and secretory genes, suggesting dedifferentiation. We identified inflammatory cytokines as a driver of this phenotype by reanalyzing public data from primary human beta cells stimulated with inflammatory cytokines in vitro. We additionally find a similar transcriptional program active in a subset of alpha cells, consistent with cell-extrinsic inflammatory cytokine signaling in vivo. Overall, we propose that this population represents a resilient beta cell phenotype, and that the transcriptional program active in these cells may identify targets for T1D prevention and reversal.