Bertocci, B. | Search bioRxiv

bioRxiv2026

Interference with MHC class I epitope trimming provides paradoxical protection from autoimmune diabetes

Polymorphism in endoplasmic reticulum antigen processing peptidases (ERAAP) that trim MHC class I ligands is associated with autoimmune diseases, but the mechanism is unknown. We analyzed the effect of Eraap deficiency in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Eraap-/- NOD mice displayed reduced and delayed diabetes, harbored splenic effector T cells unable to transfer diabetes, and exhibited a strong shift from effector to central memory T cells in attenuated islet infiltrates. Eraap deficiency increased presentation of the immunodominant epitope insulin B15-23 by beta cells but at the same time provided complete protection from diabetes to chimeras reconstituted with bone marrow encoding a CD8+ T cell recognizing this epitope. These results underline the strong impact of self-antigen presentation to CD8+ T cells in diabetes. At the same time, they highlight the complex consequences of interfering with MHC-I antigen presentation in autoimmunity and advise caution in therapeutic modulation of ERAP activity in this context.

immunology↗

bioRxiv2023

Pancreatic islet cell stress induced by insulin-degrading enzyme deficiency promotes islet regeneration and protection from autoimmune diabetes

Appropriate tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with highly variable demand for insulin synthesis. An efficient UPR ensures a sufficient beta cell mass and secretory output but can also affect beta cell resilience to autoimmune aggression. The factors regulating protein homeostasis in the face of metabolic and immune challenges are insufficiently understood. We examined beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE), a ubiquitous protease with high affinity for insulin and genetic association with type 2 diabetes. IDE deficiency induced a low-level UPR in both C57BL/6 and autoimmune non-obese diabetic (NOD) mice, associated with rapamycin-sensitive beta cell proliferation strongly enhanced by proteotoxic stress. Moreover, in NOD mice, IDE deficiency protected from spontaneous diabetes and triggered an additional independent pathway, conditional on the presence of islet inflammation but inhibited by proteotoxic stress, highlighted by strong upregulation of regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. Our findings establish a key role of IDE in islet cell protein homeostasis, identify a link between low-level UPR and proliferation, and reveal an UPR-independent anti-inflammatory islet cell response uncovered in the absence of IDE of potential interest in autoimmune diabetes.

cell biology↗