Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199264 | GEO | 2022/03/31
REPOSITORIES: GEO
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Project description:The peptides repertoire presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules, referred to as the MHC I-associated peptidome (MIP), regulates all critical events that occur during the lifetime of CD8+ T cells. The MIP presented by thymic antigen presenting cells (APCs) is crucial for shaping CD8+ T cell repertoire and self-tolerance, while the MIP presented by peripheral tissues and organs is not only involved in maintaining periphery CD8+ T cell survival and homeostasis, but also mediates immune surveillance and autoimmune responses of CD8+ T cells under pathological conditions. Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by the destruction pancreatic β cells, mediated primarily by autoreactive CD8+ T cells. Non-obese diabetic (NOD) mouse is one of important animal models of spontaneous autoimmune diabetes that shares several key features with human T1D. Here, we deeply analyzed the MIP derived from the primary tissues of thymus and pancreas in NOD mice using targeted database searches of mass spectrometry data. We demonstrated that the thymus MIP source proteins accommodated only a small portion of the transcriptome of thymus epithelial cells, and partially shared with the MIP source proteins derived from NOD mice pancreas and β cell line. The global view of the MHC I-associated self-peptides repertoire in the thymus and pancreas of NOD mice may serve as a biological reference to identify potential autoantigens targeted by autoreactive CD8+ T cells in T1D.
2022-10-14 | PXD031966 | Pride
Project description:Autoreactive CD8+ T cell plays a key role in the pathogenesis of Type 1 diabetes (T1D), but the antigen spectrum that activate autoreactive CD8+ T cells is still not completely clear. Endoplasmic reticulum stress（ERS）has been implicated in the generation of β cell autoantigens and the enhanced immune visibility of β cells to autoreactive T cells. Here, we in-depth analyzed the major histocompatibility complex class I (MHC-I) associated immunopeptidome (MIP) of islets β cell under steady-state and ERS-state, and found couples of peptides exclusively present in the MIP of β cell line under ERS state. Among them, peptide OTUB258-66 derived from ubiquitin thioesterase OTUB2 showed immunodominance in NOD mice, and autoreactive CD8+ T cells targeting OTUB258-66 were diabetogenic in NOD mice. High glucose intake upregulated the expression of OTUB2 in the pancreas and amplified the OTUB258-66-specific CD8+ T cell response in NOD mice. Repeated administration with OTUB258-66 significantly reduced the incidence of T1D in NOD mice. This study not only provides an explanation for the role of ERS induced by environmental factors such as high glucose intake in promoting β cell autoimmune injury, but also provides a novel ERS-associated β cell autoantigens for developing specific immune intervention in prevention and treatment of T1D.
2024-05-24 | PXD041227 | Pride
Project description:Aims/hypothesis AGEs are considered environmental contributors of type 1 diabetes, but the exact role AGEs play early in pathogenesis of the disease, remains unidentified. We aimed to reduce AGEs with the pharmacotherapy alagebrium chloride in MIN6N8 cells and early in life in NOD mice to determine its impact on beta cell immunogenicity, function, and disease progression. Methods MIN6N8 cells were cultured with AGEs with or without short-term alagebrium therapy to determine the effect on ER stress and beta cell antigen presentation via a reporter assay for protein responses in the unfolded protein response, the enzymatic activity of endoplasmic reticulum aminopeptidase-1 (ERAP1) and the immunopeptidome. To determine the effect of short-term alagebrium therapy on beta cells in vivo, female NOD mice were treated with alagebrium and insulin secretion, insulitis, and immune cell repertoire were studied. Adoptive transfer studies and diabetes progression studies were used to consider the impact of alagebrium on immune cell function and disease outcome. Results In MIN6N8 cells, alagebrium therapy inhibited the induction of endoplasmic reticulum (ER) stress and the activity of ERAP1 by AGE-modified proteins. Alagebrium treated-MIN6N8 cells did not change the MHC Class I presentation of known beta cell antigens but did induce proteomic changes related to ER homeostatic pathways. Prior to overt autoimmune diabetes, female NOD mice treated with alagebrium for 30-40 days had improved insulin secretion, reduced insulitis and amplified proportions of pancreatic CD8+ T cells, mature B cells and F4/80+ macrophages. Splenocytes from alagebrium-treated mice adoptively transferred disease to NODscid recipients and maintained interferon production in vitro. While partial protection of islets by alagebrium was seen following the adoptive transfer of activated NOD G9C8 transgenic TCR CD8+ T cells, alagebrium therapy in NOD mice did not reduce diabetes progression. Conclusions/interpretation Our data suggests that in experimental models of diabetes, short-term alagebrium treatment allows for beta cell improvement, and maintenance of immune cell function, which does not fully mitigate diabetes progression.
2021-06-29 | PXD025998 | Pride
Project description:Type 1 diabetes mellitus (T1D) is caused by killing of insulin producing β cells by CD8+T cells. The disease progression accelerates as glucose tolerance deteriorates suggesting that acquired factors contribute. To identify how environmental factors may lead to the expansion and pathogenicity of the diabetogenic T cells, we analyzed diabetogenic NRP-V7-reactive CD8+ T cells that recognize a peptide from the diabetes antigen IGRP in prediabetic NOD mice. There was an increase in the frequency of the NRP-V7-reactive cells coinciding with the time of glucose intolerance. The T cells persisted in hyperglycemic NOD mice maintained with an insulin pellet despite destruction of beta cells. We compared gene expression in the NRP-V7-reactive T cells to others that shared their phenotype but not selected for reactivity to diabetes antigens viral antigen reactive cells. Compared to these other cells, the NRP-V7-reactive cells exhibited gene expression of memory precursor effector cells. They had reduced cellular proliferation and were less dependent on oxidative phosphorylation. When prediabetic NOD mice were treated with 2DG to block aerobic glycolysis, there was a reduction in the diabetes antigen vs other cells of similar phenotype and loss of lymphoid cells infiltrating the islets. In addition, treatment of NOD mice with 2DG resulted in improved cell granularity. These findings identify a link between metabolic disturbances and autoreactive T cells that promotes development of autoimmune diabetes.
2016-03-17 | GSE79200 | GEO
Project description:This a model from the article:
Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease?
Maree AF, Kublik R, Finegood DT, Edelstein-Keshet L.Philos Transact A Math Phys Eng Sci.2006 May 15;364(1842):1267-82.
16608707,
Abstract:
A wave of apoptosis (programmed cell death) occurs normally in pancreatic beta-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al. 1999 Diabetes 48, 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000381 | BioModels
Project description:With the goal of identifying changes in gene expression in CD4(+) T cells during the development of diabetes in the nonobese diabetic (NOD) mouse, we used DNA microarrays to analyze gene expression in CD4(+) T cells from the pancreatic draining lymph nodes of NOD/BDC 2.5 T cell receptor transgenic and WT NOD mice at different ages. At 4 and 6 weeks of age, we found up-regulation of a number of genes that are known to be induced by IFN-alpha. IFN-alpha levels and IFN-alpha-producing plasmacytoid dendritic cells were increased in the PLNs of 3- to 4-week-old NOD mice. Moreover, blockade of IFN-alpha receptor 1 in NOD mice by a neutralizing antibody at 2-3 weeks of age significantly delayed the onset and decreased the incidence of type 1 diabetes, increased the relative number of immature dendritic cells in the PLNs, and enhanced the ability of spleen CD4(+) T cells to produce IL-4 and IL-10. These findings demonstrate that IFN-alpha in the PLNs is an essential initiator in the pathogenesis of type 1 diabetes in NOD mice. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract.
2010-06-25 | E-GEOD-15213 | biostudies-arrayexpress
Project description:Type 1 diabetes is a multigenic disease caused by T-cell mediated destruction of the insulin producing β-cells. Although conventional (targeted) approaches of identifying causative genes have advanced our knowledge of this disease, many questions remain unanswered. Using a whole molecular systems study, we unraveled the genes/molecular pathways that are altered in CD4 T-cells from young NOD mice prior to insulitis (lymphocytic infiltration into the pancreas). Many of the CD4 T-cell altered genes lie within known diabetes susceptibility regions (Idd), including several genes in the diabetes resistance region Idd13 and two genes (Khdrbs1 and Ptp4a2) in the CD4 T-cell diabetogenic activity region Idd9/11. Alterations involved apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks), inflammation and cell signaling/activation (predominant at 3 weeks), and innate and adaptive immune responses (predominant at 4 weeks). We identified several factors that may regulate these abnormalities: IRF-1, HNF4A, TP53, BCL2L1 (lies within Idd13), IFNG, IL4, IL15, and prostaglandin E2, which were common to all 3 ages; AR and IL6 to 2 and 4 weeks; and Interferon (IFN-I) and IRF-7 to 3 and 4 weeks. Others were unique to the various ages (e. g. MYC, JUN, and APP to 2 weeks; TNF, TGFB1, NFKB, ERK, and p38MAPK to 3 weeks; and IL12 and STAT4 to 4 weeks). Our data suggest that diabetes resistance genes in Idd13 and Idd9/11, and BCL2L1, IL6-AR and IFNG-IRF-1-IFN-I/IRF-7-IL12 pathways play an important role in CD4 T-cells in the early pathogenesis of autoimmune diabetes. Thus, the alternative approach of investigation at the molecular systems level has captured new information, which combined with validation studies, offers the opportunity to test hypotheses on the role played by the genes/molecular pathways identified in this study, to understand better the mechanisms of autoimmune diabetes in CD4 T-cells, and to develop new therapeutic strategies for the disease. CD4 T-cells were purified from spleen leukocytes collected from 2-, 3- and 4-week old NOD mice and two age-matched control strains, NOR, and C57BL/6, (n=5 for each strain and each age group; except NOD2wk). NOR is an insulitis- and diabetes-free control strain that shares shares ~88% of its genome with NOD mice, including the diabetogenic H2g7 MHC haplotype and several important non-MHC T1D susceptibility loci. C57BL/6 is also a diabetes-resitant strain, but it is more genetically distantly related to NOD.
2014-06-20 | E-GEOD-46600 | biostudies-arrayexpress
Project description:With the goal of identifying changes in gene expression in CD4(+) T cells during the development of diabetes in the nonobese diabetic (NOD) mouse, we used DNA microarrays to analyze gene expression in CD4(+) T cells from the pancreatic draining lymph nodes of NOD/BDC 2.5 T cell receptor transgenic and WT NOD mice at different ages. At 4 and 6 weeks of age, we found up-regulation of a number of genes that are known to be induced by IFN-alpha. IFN-alpha levels and IFN-alpha-producing plasmacytoid dendritic cells were increased in the PLNs of 3- to 4-week-old NOD mice. Moreover, blockade of IFN-alpha receptor 1 in NOD mice by a neutralizing antibody at 2-3 weeks of age significantly delayed the onset and decreased the incidence of type 1 diabetes, increased the relative number of immature dendritic cells in the PLNs, and enhanced the ability of spleen CD4(+) T cells to produce IL-4 and IL-10. These findings demonstrate that IFN-alpha in the PLNs is an essential initiator in the pathogenesis of type 1 diabetes in NOD mice.
2009-03-13 | GSE15213 | GEO
Project description:Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear if and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using non-obese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs. More IGRP-specific T cells resided in the peripheral lymphoid organs than in islets. To examine the impact of extra-islet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen presenting cells. Antigen exposure in the extra-islet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce IFNγ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.
2024-03-05 | GSE247956 | GEO
Project description:Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.
2024-05-31 | PXD048004 | Pride