IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

Aims/hypothesis IFN-alpha, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-alpha withdrawal or IFN-alpha pathway inhibition. Methods IFN-alpha-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-beta H1 cells or human islets exposed to IFN-alpha with or without the presence of Janus kinase (JAK) inhibitors. Protein expression was evaluated by western blot. Results IFN-alpha-induced expression of inflammatory and ER stress markers returned to baseline after 24-48 h following cytokine removal. In contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, when added with IFN-alpha, prevented MHC class I overexpression, but when added 24 h after IFN-alpha exposure these inhibitors failed to accelerate MHC class I return to baseline. Conclusions/interpretation IFN-alpha mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFN-alpha-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-alpha inhibitors might need to be used at very early stages of the disease to be effective.