Autophagy-Dependent Regulation of Beta Cell Stress and Immunogenicity

Abstract

Type 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. A leading hypothesis for an environmental triggering event is viral infection. Accumulating evidence suggests that defects in β-cell stress response pathways play an important role in T1D development. β-cell endoplasmic reticulum stress, oxidative stress, and senescence precede clinical onset of T1D. These β-cell stressors are linked to enhanced production of β-cell neoantigens, likely important in breaking immune tolerance in T1D pathogenesis. Autophagy is an essential pathway that mitigates cellular stress and restores homeostasis. Previously, we discovered that β-cell autophagy is impaired prior to T1D onset, implicating this pathway in T1D pathogenesis. To characterize the mechanisms by which alterations in β-cell autophagy may contribute to T1D pathogenesis, we employed a mouse model of impaired β-cell autophagy as well as pharmacological modulators of autophagy in mouse islets and human β-cells. We demonstrated that defective β-cell autophagy induces ER stress, stimulates proinflammatory cytokine production pathways, increases HLA-I presentation, and enhances islet immunogenicity. Based on these observations, we investigated mechanisms by which defective autophagy leads to increased β-cell HLA-I expression and enhanced immunogenicity. Impaired β-cell autophagy led to increased HLA-I complex formation and altered complex recycling. Modulation of autophagy further promoted lysosomal exocytosis and changes in the secretome in EndoC-βH1 cells and human islets. This included upregulation of PTPRN2, a known autoantigen in T1D, and increased secreted HLA-I complex. Alterations in the secretome also showed changes in β-cell responses to environmental stressors, including viral infection. Moreover, impaired β-cell autophagy enhanced production of proinflammatory signals involved in immune cell recruitment and activation. Overall, our findings advance our understanding of how defective autophagy shapes β-cell immunogenicity and stress responses, and highlight autophagy as a potential therapeutic target for future T1D intervention.