The diabetogenic, insulin‐specific CD8 T cell response primed in the experimental autoimmune diabetes model in RIP‐B7.1 mice

Karges, Wölfram; Rajasalu, Tarvo; Spyrantis, Andreas; Wieland, Andreas; Boehm, Bernhard O.; Schirmbeck, Reinhold

doi:10.1002/eji.200737222

Cited by 14 publications

(36 citation statements)

References 23 publications

(54 reference statements)

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“…Also, in mouse models of experimental diabetes, except for those where foreign antigens are expressed from the rat insulin promoter, most described CD8 T cell targets are peptides that bind MHC-I molecules with low affinity (29) (30). The low affinity of the diabetogenic epitope IGRP 5′UTR [7][8][9][10][11][12][13][14] , targeted in our model (Figure 4), further supports this notion.…”

Section: Discussionsupporting

confidence: 73%

Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases

Zaiss

Bekker

University

et al. 2012

Molecular Immunology

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Section: Discussionsupporting

confidence: 73%

Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases

Zaiss

Bekker

University

et al. 2012

Molecular Immunology

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“…Destruction of pancreatic ␤ cells depended on IFN-␥-producing, ppins-specific CD8 T cells (15). We previously showed that RIP-B7.1 mice deficient in IFN-␥ could not induce EAD after immunization with pCI/ppins DNA (15). It has been suggested that IFN-␥ may directly mediate ␤ cell destruction and/or facilitate MHC class I-restricted presentation of the diabetogenic epitope(s) to CD8 T cells (16 -18).…”

Section: T Ype 1 Diabetes Mellitus (T1d)mentioning

confidence: 98%

“…We used RIP-B7.1 mice (11) that express the costimulator molecule B7.1 (CD80) on pancreatic ␤ cells to characterize the specificity and diabetogenic potential of CD8 T cell responses (12)(13)(14)(15). Studies have shown that DNA vectors encoding murine preproinsulin-II (ppins) efficiently induced CD8 T cell-dependent experimental autoimmune diabetes (EAD) in RIP-B7.1 (but not B6) mice within 3-4 wk after immunization (15). The EAD was characterized by insulitis, progressive invasion of T cells into the islets, ␤ cell destruction, and hyperglycemia (15).…”

Section: T Ype 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

“…Studies have shown that DNA vectors encoding murine preproinsulin-II (ppins) efficiently induced CD8 T cell-dependent experimental autoimmune diabetes (EAD) in RIP-B7.1 (but not B6) mice within 3-4 wk after immunization (15). The EAD was characterized by insulitis, progressive invasion of T cells into the islets, ␤ cell destruction, and hyperglycemia (15). Destruction of pancreatic ␤ cells depended on IFN-␥-producing, ppins-specific CD8 T cells (15).…”

Section: T Ype 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

“…The EAD was characterized by insulitis, progressive invasion of T cells into the islets, ␤ cell destruction, and hyperglycemia (15). Destruction of pancreatic ␤ cells depended on IFN-␥-producing, ppins-specific CD8 T cells (15). We previously showed that RIP-B7.1 mice deficient in IFN-␥ could not induce EAD after immunization with pCI/ppins DNA (15).…”

Section: T Ype 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

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Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses

Brosi

Reiser

Rajasalu

et al. 2009

The Journal of Immunology

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RIP-B7.1 mice express the costimulator molecule B7.1 (CD80) on pancreatic β cells and are a well-established model for studying de novo induction of diabetogenic CD8 T cells. Immunization of RIP-B7.1 mice with preproinsulin (ppins)-encoding plasmid DNA efficiently induces experimental autoimmune diabetes (EAD). EAD is associated with an influx of CD8 T cells specific for the Kb/A12–21 epitope into the pancreatic islets and the subsequent destruction of β cells. In this study, we used this model to investigate how ppins-derived Ags are expressed and processed to prime diabetogenic, Kb/A12–21-specific CD8 T cells. Targeting the Kb/A12–21 epitope, the insulin A chain, or the ppins to the endoplasmic reticulum (ER) (but not to the cytosol and/or nucleus) efficiently elicited Kb/A12–21-specific CD8 T cell responses. The Kb/A12–21 epitope represents the COOH terminus of the ppins molecule and, hence, did not require COOH-terminal processing before binding its restriction element in the ER. However, Kb/A12–21-specific CD8 T cells were also induced by COOH-terminally extended ppins-specific polypeptides expressed in the ER, indicating that the epitope position at the COOH terminus is less important for its diabetogenicity than is targeting the Ag to the ER. The Kb/A12–21 epitope had a low avidity for Kb molecules. When epitopes of unrelated Ags were coprimed at the same site of Ag delivery, “strong” Kb-restricted (but not Db-restricted) CD8 T cell responses led to the suppression of Kb/A12–21-specific CD8 T cell priming and reduced EAD. Thus, direct expression and processing of the “weak” Kb/A12–21 epitope in the ER favor priming of autoreactive CD8 T cells.

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PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

et al. 2016

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Aims/hypothesisA strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM.MethodsTwo groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements.ResultsPAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death.Conclusions/interpretationThe coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3864-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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The diabetogenic, insulin‐specific CD8 T cell response primed in the experimental autoimmune diabetes model in RIP‐B7.1 mice

Cited by 14 publications

References 23 publications

Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases

Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases

Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

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