What does this research mean for the field?

Exposure to inflammatory cytokines and coxsackievirus triggers distinct, cell-type-specific gene regulatory dynamics and transcript isoform shifts across human pancreatic islet cell populations. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

The aim is to understand how pancreatic islet cells respond to inflammatory and viral stimuli and the associated gene regulatory dynamics.

June 7, 2026

1083-OR: Multiomic Dissection of Human Pancreatic Islet Responses to Inflammatory and Viral Stimuli Reveals Cell-Type–Specific Regulatory Dynamics Relevant to Type 1 Diabetes

Key Points

The aim is to understand how pancreatic islet cells respond to inflammatory and viral stimuli and the associated gene regulatory dynamics.
Leveraged 10x Genomics multiome single nucleus sequencing to profile islet responses in 55 donors.
Profiled transcriptomes and chromatin accessibility under control conditions and after 48-hour exposure to cytokines or coxsackievirus.
Performed long-read sequencing on selected multiome cDNA libraries for detailed transcript diversity.
Identified 135,565 high quality nuclei from nine pancreatic cell types with exposure-specific pathways.
In ductal cells, cytokine treatment significantly upregulated transcript isoform ENST00000297350.9 with log2 fold change = 2.0, p = 1.9 × 10−5.
Established cell-type-specific gene regulatory dynamics relevant for immune-β-cell interactions in T1D.

Abstract

Introduction and Objective: Intra-islet responses to proinflammatory stressors are central to the pathogenesis of type 1 diabetes (T1D), yet the gene-regulatory dynamics triggered by inflammatory and viral insults in islet cell populations are not fully understood. Methods: Here, we leveraged 10x Genomics multiome single nucleus sequencing to jointly profile transcriptomes and chromatin accessibility in human islets from 55 donors under control conditions and following 48-hour exposure to either a pro-inflammatory cytokine cocktail (TNFα, IFN-γ, and IL-1β) or coxsackievirus. To capture transcript diversity at higher resolution, we performed long-read sequencing (Oxford Nanopore) on selected multiome cDNA libraries. Results: By multiplexing samples with a randomized block design and implementing robust quality control and data integration pipelines, we identified 135,565 high quality nuclei and resolved exposure-specific response pathways in nine pancreatic cell types - acinar (41,260 nuclei), ductal (35,662), alpha (19,646), beta (29,419), delta (2,555), gamma (1,401), immune (709), stellate (2,204), and endothelial (3,709) - including dynamic shifts in isoform expression in response to treatments. For example, in ductal cells, cytokine treatment upregulated the transcript isoform ENST00000297350.9 (log2 fold change = 2.0, p = 1.9 × 10−5), a splice variant of TNFRSF11B (osteoprotegerin), a member of the TNF receptor superfamily, consistent with previous reports of cytokine-mediated induction in islets. Conclusion: Through ongoing long-read sequencing and integration with joint chromatin accessibility profiling, we are modeling cell-type-specific gene regulatory dynamics that orchestrate islet response to proinflammatory stimuli. This resource highlights transcripts and regulatory nodes with potential functional relevance for immune-β-cell crosstalk, offering mechanistic insights to inform pathogenic immune-islet interactions in T1D. Disclosure C.C. Robertson: None. Z. Meng: None. S. Lin: None. A.K. Huber: None. X. Wang: None. P. Orchard: None. M.R. Erdos: None. F. Collins: Board Member; Current; ImmunoBrain Checkpoint, Inc. S. Chen: Stock/Shareholder; Current; iOrganBio Inc. Stock/Shareholder; Ended; Oncobeat. S. Parker: Research Support; Current; Pfizer Inc. Consultant; Ended; Novo Nordisk. Funding National Institutes of Health (5U01DK127777)

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