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bioRxiv · 10.64898/2026.02.19.706793

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

Bertocci, B.·Waeckel-Enee, E.·Keelan, N.·You, S.·David, P.·van Endert, P.
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Abstract

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.

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Bertocci, B., Waeckel-Enee, E., Keelan, N., You, S., David, P., van Endert, P.. 2026-02-20. Interference with MHC class I epitope trimming provides paradoxical protection from autoimmune diabetes. https://doi.org/10.64898/2026.02.19.706793

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