Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes

Bessard, Marie-Andrée, Moser, Anna, Waeckel-Énée, Emmanuelle, Lindo, Vivian, Gdoura, Abdelaziz, You, Sylvaine, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845, Greer, Fiona and van Endert, Peter 2024. Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes. Frontiers in Immunology 15 , 1474453. 10.3389/fimmu.2024.1474453

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Abstract

Type 1 diabetes results from the destruction of pancreatic beta cells by autoreactive T cells. As an autoantigen with extremely high expression in beta cells, insulin triggers and sustains the autoimmune CD4+ and CD8+ T cell responses and islet inflammation. We have previously shown that deficiency for insulin-degrading enzyme (IDE), a ubiquitous cytosolic protease with very high affinity for insulin, induces endoplasmic reticulum (ER) stress and proliferation in islet cells and protects non-obese diabetic mice (NOD) from diabetes. Here we wondered whether IDE deficiency affects autoreactive CD8+ T cell responses to insulin and thereby immune pathogenesis in NOD mice. We find that Ide-/- NOD harbor fewer diabetogenic T cells and reduced numbers of CD8+ T cells recognizing the dominant autoantigen insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Using in vitro digestions and cellular antigen presentation assays, we show that generation of the dominant insulin epitope B15-23 involves both the proteasome and IDE. IDE deficiency attenuates MHC-I presentation of the immunodominant insulin epitope by beta cells to cognate CD8+ T cells. Consequently, Ide-/- islets display reduced susceptibility to autoimmune destruction upon grafting, and to killing by insulin-specific CD8+ T cells. Moreover, Ide-/- mice are partly resistant to disease transfer by CD8+ T cells specific for insulin but not for IGRP. Thus, IDE has a dual role in beta cells, regulating ER stress and proliferation while at the same time promoting insulin-directed autoreactive CD8+ T cell responses.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Frontiers Media
Date of First Compliant Deposit:	27 November 2024
Date of Acceptance:	25 October 2024
Last Modified:	27 Nov 2024 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/174324

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