This week’s journal club focuses on a study from Frontiers in Immunology (2025) aiming to assess the role of autophagy in b-cell health and survival, and whether defects in autophagy render islets more immunogenic.
revisited by Shayla Sharmine
Type 1 diabetes(T1D) arises from autoimmune-mediated pancreatic beta cell destruction triggered by a combination of genetic and environmental factors. This research aimed to investigate the mechanisms contributing to alternating beta-cell autophagy in the pathogenesis of type 1 diabetes (T1D). To achieve their aim, Austin et al. hypothesized that defective beta-cell autophagy interferes with the β-cell-immune cell interface, leading to activation or exacerbation of the immune response towards T1D.
To test the hypothesis, they generated ATG7fl/fl mice crossed with Ins1cre mice using the Cre-Lox system, resulting in mice with impaired autophagy in pancreatic β-cells. Phenotypical assessments, such as blood glucose levels and glucose tolerance, as well as molecular-level assessments, including transcriptomics and proteomics, were performed on isolated islets. MHC-1/HLA-1 expression was tested in mice and human β-cells under basal and IFN-α-stimulated conditions following pharmacological inhibition or stimulation of autophagy. Islet cells were co-cultured with splenocytes containing diabetogenic CD4+ T cells to test immunogenicity.
Results show that beta cell ATC7fl/fl mice developed diabetes between 11- 15 weeks of age. HMZ islets showed upregulation of inflammatory and ER stress pathways, downregulation of beta-cell protective genes (including REG family, cholesterol/lipid metabolism). Proteomics analysis reconfirmed the ER stress markers and antigen-processing pathways. As a part of the immune response, ATG7-deficient beta cells containing islets had enhanced MHC-1 expression and CD45+ immune cells infiltration. In vitro experiment on EndoC-βH1 cells with inhibited autophagy exhibited increased HLA-1, while stimulation of lysosome function reduced it. Co-culture experiment with splenocytes demonstrated higher T cell activation in the presence of autophagy-impaired islet cells.
Altogether, the findings suggest that defective β-cell autophagy induces ER stress, promotes antigen presentation, and increases β-cell susceptibility to immune destruction by accelerating autoimmuno recognition, leading to the destruction of β-cells, contributing to T1D development. Therefore, this study provides evidence and insights into β-cell autophagy as a potential therapeutic target for preventing or delaying T1D pathogenesis.
Continue your reading here:
Austin MC, Muralidharan C, Roy S, Crowder JJ, Piganelli JD, Linnemann AK. (2025). “Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity” Frontiers in Immunology 2025 Jan 29;16:1504583. doi: 10.3389/fimmu.2025.1504583. eCollection 2025. PMID: 39944686