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ScRNAseq analysis of data from patients with T1D and healthy donors

ABSTRACT: Type 1 diabetes (T1D) arises from loss of immune tolerance to pancreatic β-cells, yet its immunologic drivers remain unclear. We performed single-cell transcriptomic profiling of peripheral T cells from children newly diagnosed with T1D, the same children one year later, and healthy controls. At diagnosis, T1D was marked by broadly reduced effector and cytotoxic programs and increased stemness-related signatures across multiple T cell subsets, alongside impaired regulatory features in both Tregs and TR3-56 cells. Flow cytometry from the same cohort and reanalysis of public datasets confirmed these patterns. Together, these data suggest that T1D involves defective T cell effector differentiation and compromised regulatory control, contributing to immune dysregulation and loss of self-tolerance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309970 | GEO | 2025/11/15

REPOSITORIES: GEO

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Project description:Aims/Hypothesis: Type 1 diabetes (T1D) is an autoimmune disease marked by the destruction of beta cells in the pancreatic islets, with an incomplete picture of disease pathogenesis/progression and a lack of definitive cure. A recent finding linked pancreatic ductal cells of T1D donors with elevated levels of human leukocyte antigen (HLA) Class II molecules; however, the causal relationship and functional significance of this finding remain unknown. Because HLA Class II molecules are typically expressed by professional antigen presenting cells (APCs), this raises the possibility of ductal cells functioning as non-professional APCs. In this study, we test the hypothesis that non-T1D ductal cells are responsive to T1D-associated proinflammatory cytokines, TNF-α, IL-1β, and IFN-γ, and can act as non-professional APCs. Methods: Pancreatic exocrine cells, after the removal of islets, were obtained from cadaveric donors without apparent diseases and with appropriate consent. Cells were cryopreserved, thawed into a defined culture medium tailored to support ductal cell survival in a 3D suspension culture system. Ductal cells were exposed to various doses of cytokines for 48 hours and analyzed for gene and protein expression, using qRT-PCR, bulk-RNAseq, flow cytometry and Western blot analyses. Functional ability of cytokine-treated ductal cells to present an exogenous autoantigen (glutamate decarboxylase 65kD isoform [GAD65]) to T cells was tested using a GAD65-specific autoreactive CD4+ T cell clone (named BRI4.13) isolated from a T1D donor. Results: We found that within 48 hours a combination of TNF-α, IL-1β, and IFN-γ stimulated the expression of HLA Class II, co-stimulatory, and antigen-processing molecules at mRNA and protein levels in non-T1D ductal cells. Bulk RNAseq analysis showed that cytokines most significantly upregulated biological pathways in “antigen processing and presentation” and “T1D”. When cytokine-treated ductal cells were pulsed with an exogenous GAD65 peptide and cocultured with the BRI4.13 T cells, these T cells became activated and proliferated. Unexpectedly, we also found ~1% of KRT19+ ductal cells express GAD protein endogenously. Conclusions/interpretation: These results demonstrate that non-diseased primary ductal cells are sensitive to TNF-α, IL-1β, and IFN-γ stimulation, and can upregulate APC molecules and function in antigen presentation to autoreactive CD4+ T cells. To the best of our knowledge, our results provide the first evidence demonstrating antigen presentation by non-T1D human ductal cells to T cells, which implicate ductal cells in contributing to T1D progression.

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ScRNAseq analysis of data from patients with T1D and healthy donors

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