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

Autor: Bessard MA; Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, France., Moser A; Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, France., Waeckel-Énée E; Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, France., Lindo V; M-SCAN, Wokingham, United Kingdom., Gdoura A; Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, France., You S; Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Cochin, Paris, France., Wong FS; Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, United Kingdom., Greer F; M-SCAN, Wokingham, United Kingdom., van Endert P; Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, France.; Service Immunologie Biologique, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants Malades, Paris, France.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2024 Nov 12; Vol. 15, pp. 1474453. Date of Electronic Publication: 2024 Nov 12 (Print Publication: 2024).
DOI: 10.3389/fimmu.2024.1474453
Abstrakt: 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 B 15-23 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.
Competing Interests: Authors VL and FG were employed by company M-SCAN. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Bessard, Moser, Waeckel-Énée, Lindo, Gdoura, You, Wong, Greer and van Endert.)
Databáze: MEDLINE
Externí odkaz: