Diabetologia · 2026
Human pancreatic ductal cells from non-diabetic donors function as non-professional antigen-presenting cells upon inflammatory cytokine exposure.
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Erdem Neslihan, Arribas-Layton David, Zook Heather N, O'Meally Denis, Mares Jacob, Quijano Janine C, Donohue Cecile, Ortiz Jose A, Jou Kevin, Vasavada Rupangi C, Montero Enrique, Kaddis John S, Reijonen Helena, Ku Hsun Teresa
Аннотация
AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disease marked by the destruction of beta cells in pancreatic islets, with an incomplete picture of disease progression and a lack of a definitive cure. A recent finding linked pancreatic ductal cells of type 1 diabetic 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 ductal cells are responsive to type 1 diabetes-associated proinflammatory cytokines, TNF-α, IL-1β and IFN-γ, and can act as non-professional APCs.
METHODS: Pancreatic exocrine cells were obtained from cadaveric donors without diabetes following islet removal. Cells were cryopreserved and 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 h and analysed for gene and protein expression, using quantitative PCR with reverse transcription, bulk RNA-seq, flow cytometry and western blot analyses. Correlation between cytokine response and APC-related gene expression was evaluated using publicly available single-cell RNA-seq datasets from 86 donors. The functional ability of cytokine-treated ductal cells to present an exogenous autoantigen (glutamic acid decarboxylase 65 kDa isoform [GAD65]) to T cells was tested using a GAD65-specific autoreactive CD4+ T cell clone (BRI-4.13) isolated from a type 1 diabetic donor.
RESULTS: Within 48 h, a combination of TNF-α, IL-1β and IFN-γ stimulated mRNA and protein expression of HLA class II, co-stimulatory and antigen-processing molecules in non-diabetic ductal cells. Bulk RNA-seq analysis showed that cytokines significantly upregulated biological pathways in 'antigen processing and presentation' and 'type 1 diabetes'. Single-cell RNA-seq analysis revealed a positive correlation between cytokine response and APC gene expression in human pancreatic ductal cells. Cytokine-treated ductal cells pulsed with exogenous GAD65 peptide activated and induced proliferation of BRI-4.13 T cells. Unexpectedly, ~0.9% of KRT19+ ductal cells expressed GAD protein endogenously, and 26.6% of KRT19+GAD+ ductal cells expressed the endocrine marker CHGA.
CONCLUSIONS/INTERPRETATION: These results demonstrate that non-diseased primary ductal cells respond to TNF-α, IL-1β and IFN-γ by upregulating APC molecules and presenting antigen to autoreactive CD4+ T cells. To the best of our knowledge, our results provide the first evidence that non-diabetic human ductal cells can present antigen to T cells, which implicates ductal cells in contributing to type 1 diabetes progression.
METHODS: Pancreatic exocrine cells were obtained from cadaveric donors without diabetes following islet removal. Cells were cryopreserved and 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 h and analysed for gene and protein expression, using quantitative PCR with reverse transcription, bulk RNA-seq, flow cytometry and western blot analyses. Correlation between cytokine response and APC-related gene expression was evaluated using publicly available single-cell RNA-seq datasets from 86 donors. The functional ability of cytokine-treated ductal cells to present an exogenous autoantigen (glutamic acid decarboxylase 65 kDa isoform [GAD65]) to T cells was tested using a GAD65-specific autoreactive CD4+ T cell clone (BRI-4.13) isolated from a type 1 diabetic donor.
RESULTS: Within 48 h, a combination of TNF-α, IL-1β and IFN-γ stimulated mRNA and protein expression of HLA class II, co-stimulatory and antigen-processing molecules in non-diabetic ductal cells. Bulk RNA-seq analysis showed that cytokines significantly upregulated biological pathways in 'antigen processing and presentation' and 'type 1 diabetes'. Single-cell RNA-seq analysis revealed a positive correlation between cytokine response and APC gene expression in human pancreatic ductal cells. Cytokine-treated ductal cells pulsed with exogenous GAD65 peptide activated and induced proliferation of BRI-4.13 T cells. Unexpectedly, ~0.9% of KRT19+ ductal cells expressed GAD protein endogenously, and 26.6% of KRT19+GAD+ ductal cells expressed the endocrine marker CHGA.
CONCLUSIONS/INTERPRETATION: These results demonstrate that non-diseased primary ductal cells respond to TNF-α, IL-1β and IFN-γ by upregulating APC molecules and presenting antigen to autoreactive CD4+ T cells. To the best of our knowledge, our results provide the first evidence that non-diabetic human ductal cells can present antigen to T cells, which implicates ductal cells in contributing to type 1 diabetes progression.