Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes
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...
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Frontiers Media S.A.
2024-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1474453/full |
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| author | Marie-Andrée Bessard Anna Moser Emmanuelle Waeckel-Énée Vivian Lindo Abdelaziz Gdoura Sylvaine You F. Susan Wong Fiona Greer Peter van Endert Peter van Endert |
| author_facet | Marie-Andrée Bessard Anna Moser Emmanuelle Waeckel-Énée Vivian Lindo Abdelaziz Gdoura Sylvaine You F. Susan Wong Fiona Greer Peter van Endert Peter van Endert |
| author_sort | Marie-Andrée Bessard |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4493069f3b8a4b9f9080e9bef49ca1c2 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-4493069f3b8a4b9f9080e9bef49ca1c22024-11-12T06:15:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-11-011510.3389/fimmu.2024.14744531474453Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetesMarie-Andrée Bessard0Anna Moser1Emmanuelle Waeckel-Énée2Vivian Lindo3Abdelaziz Gdoura4Sylvaine You5F. Susan Wong6Fiona Greer7Peter van Endert8Peter van Endert9Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, FranceUniversité Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, FranceUniversité Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, FranceM-SCAN, Wokingham, United KingdomUniversité Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, FranceUniversité Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Cochin, Paris, FranceInstitute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, United KingdomM-SCAN, Wokingham, United KingdomUniversité Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, FranceService Immunologie Biologique, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants Malades, Paris, FranceType 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1474453/fulltype 1 diabetesinsulinantigen presentationantigen processingnon-obese diabetic mouseCD8+ T cell |
| spellingShingle | Marie-Andrée Bessard Anna Moser Emmanuelle Waeckel-Énée Vivian Lindo Abdelaziz Gdoura Sylvaine You F. Susan Wong Fiona Greer Peter van Endert Peter van Endert Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes Frontiers in Immunology type 1 diabetes insulin antigen presentation antigen processing non-obese diabetic mouse CD8+ T cell |
| title | Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes |
| title_full | Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes |
| title_fullStr | Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes |
| title_full_unstemmed | Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes |
| title_short | Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes |
| title_sort | insulin degrading enzyme regulates insulin directed cellular autoimmunity in murine type 1 diabetes |
| topic | type 1 diabetes insulin antigen presentation antigen processing non-obese diabetic mouse CD8+ T cell |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1474453/full |
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