The mechanisms by which β-cells contribute to their own destruction in the pathogenesis of type 1 diabetes mellitus (T1DM) are unclear. A study in Cell Metabolism now shows that deletion of the unfolded protein response (UPR) sensor IRE1α in β-cells triggers a transient β-cell dedifferentiation and prevents T1DM in a mouse model.
The UPR enables a cell to adapt to substantial endoplasmic reticulum (ER) stress. However, long-term ER stress can cause the UPR to become pro-apoptotic. Furthermore, the UPR is impaired in preclinical models of T1DM and in humans with T1DM. Using the non-obese diabetic (NOD) mouse model of T1DM, Feyza Engin and colleagues generated a mutant in which IRE1α was deleted from β-cells in mouse pups, before the development of insulitis (IRE1αβ–/– NOD mice). Islet morphology and architecture was assessed, islet cells were immunophenotyped and RNA sequencing was carried out on intact islets as well as on single islet cells.
“IRE1α deletion in NOD β-cells before insulitis causes a transient dedifferentiation of β-cells, and these dedifferentiated β-cells show diminished expression of β-cell autoantigens and MHC class I molecules, while they increase their expression of immune inhibitory markers,” explains corresponding author Engin. Previous work found that deletion of IRE1α in prenatal or adult β-cells was associated with a diabetic phenotype. By contrast, the IRE1αβ–/– NOD mice showed only transient hyperglycaemia and were protected from T1DM up to 50 weeks of age.
Adoptive transfer experiments were carried out, transferring T cells from IRE1αβ–/– NOD mice or control mice to immunodeficient NOD Rag1–/– mice. Recipient mice became diabetic 20 weeks after cell transfer if receiving T cells from control mice, whereas they did not develop diabetes mellitus if they received T cells from IRE1αβ–/– NOD mice. “IRE1αβ–/– NOD mice exhibit impaired T cell diabetogenic activity, which leads to protection from autoimmune destruction and diabetes mellitus,” says Engin. Of note, the pancreas of IRE1αβ–/– NOD mice had substantially reduced numbers of CD8+ T cells compared with control mice. By contrast, no significant alterations were observed in the levels of CD4+ T cells, B cells or macrophages. These findings suggest that modulating the UPR in β-cells before the immune infiltration can induce β-cell dedifferentiation that triggers immune tolerance and protects against disease.
“Whether stressed human β-cells adopt a similar mechanism for stress adaptation and escape from immune attack needs to be tested,” concludes Engin. “If this finding is replicated, then there might be a critical therapeutic window for intervention specifically for autoantibody-positive high-risk individuals to briefly alter their β-cell identity, induce immune tolerance and prevent T1DM.”
Lee, H. et al. Beta cell dedifferentiation induced by IRE1a deletion prevents type 1 diabetes. Cell Metab. https://doi.org/10.1016/j.cmet.2020.03.002 (2020)
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Starling, S. β-cell dedifferentiation prior to insulitis prevents T1DM. Nat Rev Endocrinol 16, 301 (2020). https://doi.org/10.1038/s41574-020-0358-4