Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes

Wong, F. Susan; Siew, Lai Khai; Scott, G.; Thomas, Ian J.; Chapman, Stephen J.; Viret, Christophe; Li, Wen

doi:10.2337/db08-0800

Cited by 67 publications

(95 citation statements)

References 51 publications

(71 reference statements)

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“…In more recent years, insulin B [15][16][17][18][19][20][21][22][23] and isletspecific glucose-6-phophatase catalytic subunit-related protein (IGRP) 206-214 have emerged as major epitopes targeted by autoreactive CD8 + T cells [9]. Diabetes is induced when T-cell clones recognizing these sequences are transferred into healthy mice [10,11] or when transgenic T cells are primed by these epitopes in vivo [12,13]. Tracking of circulating IGRP-specific cells is able to predict subsequent diabetes development in NOD mice [14].…”

Section: Introductionmentioning

confidence: 99%

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

2012

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Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-weekold NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8 + T cells recognizing the immunodominant epitopes insulin B 15-23 and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [206][207][208][209][210][211][212][213][214] . Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high-but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials.Keywords: Insulin r NOD mouse r Prevention r T cells r Type 1 diabetes IntroductionType 1 diabetes (T1D) is an autoimmune disease in which failures in central and peripheral tolerance mechanisms lead to T-cellmediated destruction of insulin-producing β cells. Several β-cell Ags have been identified, among which insulin and its precursor (pre)proinsulin ((pre)PI) are major targets of islet-reactive T cells, both in humans [1] and in NOD mice [2]. This led to the Correspondence: Dr. Roberto Mallone e-mail: roberto.mallone@inserm.fr hypothesis that subcutaneous insulin administration could prevent disease, the rationale of which is twofold. First, insulin administration could induce a state of "β-cell rest" that would make β cells less vulnerable to metabolic stress, apoptosis [3], and possibly to immune-mediated destruction [4]. Second, repeated subcutaneous insulin injections could act as a vaccination protocol potentially restoring immune tolerance [5]. The relative role of these two putative mechanisms remains unsettled.Studies in the NOD mouse showed that subcutaneously administered insulin, started prior to disease development, is capable of preventing insulitis and diabetes [6]. This observation prompted the Diabetes Prevention Trial-Type 1 (DPT-1) [7] Eur. J. Immunol. 2012. 42: 1553-1561 developing disease [8]. However, both trials were unsuccessful, as no difference in T1D incidence was observed between insulinand placebo-treated individuals [7,8].It is still not clear why this translation from animal studies to human clinical trials fail...

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Section: Introductionmentioning

confidence: 99%

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

2012

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“…Mice NOD mice, originally from the NOD/CaJ colony at Yale University, and G9 TCR transgenic mice 47 have been bred at Cardiff University for 5 years. NY8.3 TCR transgenic mice 48 were purchased from Jackson Laboratory.…”

Section: In Vitro Transcription and Electroporation Of Mrnamentioning

confidence: 99%

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

et al. 2017

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“…Production of antigenic epitopes was read out using TCRtransgenic G9C8 CD8 + T cells with specificity for the H2-K drestricted T cell epitope insulin B [15][16][17][18][19][20][21][22][23] (27), an epitope with immunodominant status in the NOD mouse that is recognized by diabetogenic T cells found in pancreatic islet infiltrates (28). In vitro activated and restimulated G9C8 T cells secrete IFN-g upon stimulation with 10 26 M cognate peptide and H2-K d APCs (Fig.…”

Section: Assay Measuring T Cell Stimulation By Transfectants Expressimentioning

confidence: 99%

Endoplasmic Reticulum Targeting Alters Regulation of Expression and Antigen Presentation of Proinsulin

Hsu

Janssen

Lawand

et al. 2014

The Journal of Immunology

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Peptide ligands presented by MHC class I (MHC-I) molecules are produced by degradation of cytosolic and nuclear, but also endoplasmic reticulum (ER)–resident, proteins by the proteasome. However, Ag processing of ER proteins remains little characterized. Studying processing and presentation of proinsulin, which plays a pivotal role in autoimmune diabetes, we found that targeting to the ER has profound effects not only on how proinsulin is degraded, but also on regulation of its cellular levels. While proteasome inhibition inhibited degradation and presentation of cytosolic proinsulin, as expected, it reduced the abundance of ER-targeted proinsulin. This targeting and protein modifications modifying protein half-life also had profound effects on MHC-I presentation and proteolytic processing of proinsulin. Thus, presentation of stable luminal forms was inefficient but enhanced by proteasome inhibition, whereas that of unstable luminal forms and of a cytosolic form were more efficient and compromised by proteasome inhibitors. Distinct stability of peptide MHC complexes produced from cytosolic and luminal proinsulin suggests that different proteolytic activities process the two Ag forms. Thus, both structural features and subcellular targeting of Ags can have strong effects on the processing pathways engaged by MHC-I–restricted Ags, and on the efficiency and regulation of their presentation.

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Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes

Cited by 67 publications

References 51 publications

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

Endoplasmic Reticulum Targeting Alters Regulation of Expression and Antigen Presentation of Proinsulin

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