Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Characterization of immune cells infiltrating islets using scRNA-seq

ABSTRACT: In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing β cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of β-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined. Here we used single-cell RNA sequencing to gain further insight into the phenotypic complexity of islet-infiltrating CD8 T cells in NOD mice. We identified two functionally distinct subsets of activated CD8 T cells, CD44highTCF1+CXCR6- and CD44highTCF1-CXCR6+, in islets of prediabetic NOD mice. Compared to CD44highTCF1+CXCR6- CD8 T cells, the CD44highTCF1-CXCR6+ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44highTCF1+CXCR6- CD8 T cells, through continuous generation of the CD44highTCF1-CXCR6+ subset, were more capable than the latter population to promote insulitis and the development of T1D. We further showed that direct interleukin-27 (IL-27) signaling in CD8 T cells promoted the generation of terminal effectors from the CD44highTCF1+CXCR6- population. These results indicate that islet CD44highTCF1+CXCR6- CD8 T cells are a progenitor-like subset with self-renewing capacity and under an IL-27 controlled mechanism they differentiate into the CD44highTCF1-CXCR6+ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE155593 | GEO | 2021/08/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Ubiquitin Thioesterase OTUB2 is An Endoplasmic Reticulum Stress-associated β Cell Autoantigen Targeted by CD8+ T cells in Type 1 Diabetes

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

Proteomic identification of MHC class I-associated peptidome derived from non-obese diabetic mouse thymus and pancreas

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

Increased β-cell proliferation prior to immune-cell invasion prevents progression of type 1 diabetes

Project description:Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D. Here we report that enhancing β-cell mass in female NOD mice early in life (prior to weaning) results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. We observed that a model exhibiting β-cell hyperplasia on the NOD background (NOD-LIRKO) displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival of NOD-LIRKO islets even upon exposure to diabetogenic splenocytes in vivo. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented diabetes development in pre-diabetic NOD mice, while conversely, similar protective outcomes were obtained when NOD-LIRKO splenocytes were adoptively transferred after mixing them with diabetogenic NOD splenocytes in a dose-dependent manner. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population in the NOD-LIRKO mice was observed to drive the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with a downregulation of key mediators of cellular function, upregulation of apoptosis and activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data provide novel evidence that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

2019-03-29 | GSE128315 | GEO

RNA-seq of islet-specific CD8 T cells in the spleen and pancreatic islets

Project description:T cells infiltrate pancreatic islets during the progression of type 1 diabetes (T1D) but their differentiation states have not been completely defined. We used unbiased single-cell RNA sequencing analyses to gain further insight into the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice. In the CD4 T cell compartment, we identified naïve, memory, and regulatory T cells, as well as multiple Il21 expressing effector subsets positive for markers indicative of Th1 and Tfh cells. In CD8 T cells, we identified two activated subsets in addition to naïve cells. The two activated islet CD8 T cell subsets respectively resemble the self-renewing progenitor cells and the terminally differentiated/exhausted effectors during chronic lymphocytic choriomeningitis virus infection. We also identified a BATF-driven transcriptional signature promoting the diabetogenic activity of islet-infiltrating β cell autoreactive CD8 T effectors. Our results provide a useful resource for understanding T cell differentiation programs in T1D.

2024-01-22 | GSE125454 | GEO

RNA-seq of BATF-overexpressing CD8 T cells in vitro

2024-01-22 | GSE125452 | GEO

Genome-Wide Gene Expression Profiles in the Pancreatic Lymph Nodes of non-obese diabetic (NOD) mice

Project description:Type 1 diabetes (T1D) is a polygenic autoimmune disorder caused by autoreactive T cells that recognize pancreatic islet antigens and subsequently destroy insulin-producing β-cells. Pancreatic lymph nodes (PLN) are an essential site for the development of T1D, where tolerance to pancreatic self-antigens is first broken and the autoimmune responses are amplified. The purpose of this study was to identify candidate genes and pathways in the PLN that may contribute to the pathogenesis of T1D using a mouse model of T1D. Genome-wide gene expression was measured in individual NOD PLN at 10 days (n=6), 4 weeks (n=6) or 12 weeks of age (n=5), against a pooled sample of age-matched NOD.B10 PLN as the control (n≥6), using Agilent Whole Mouse Genome Microarrays.

2015-03-09 | E-GEOD-66658 | biostudies-arrayexpress

Comparison of gene expression in NOD versus NOD.NOR-Chr4 (NR4) splenic B cells.

Project description:Type 1 Diabetes (T1D) in humans and the non-obese diabetic (NOD) mouse model results from autoreactive T cell destruction of pancreatic beta cells. A pathogenic role for B lymphocytes (B cells) in T1D first became evident when NOD mice made deficient in this population through introduction of an inactivated Igµ heavy chain gene (NOD.Igµnull) or chronic treatment with anti-IgM antibodies were strongly protected from disease. We produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31Mb congenic region from rs3674285 to D4Mit127 on distal Chr. 4 (termed NOD.NOR-Chr4 (NR4)) containing disease resistance alleles decreasing the pathogenic activity of autoreactive B cells. Microarrays were conducted on B cells purified from spleens of NOD and NR4 mice to highlight differentially expressed genes within the distal Chr. 4 locus. B cells were either cultured in media alone (unstimulated) or with BCR cross-linking anti-IgM-F(ab’)2 fragments (stimulated) for 2h before RNA was extracted for transcript analysis.

2012-06-08 | GSE37294 | GEO

Nfkbid represents an Idd7 locus gene contributing to impaired thymic deletion of CD8 T-cells in NOD mice

Project description:In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T-cells recognizing pancreatic ß-cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed the common H2-Kd and/or H2-Db class I molecules expressed by this strain acquire an aberrant ability to mediate pathogenic CD8 T-cell responses through interactions with T1D susceptibility (Idd) genes outside the MHC. A gene(s) mapping to the Idd7 locus on proximal Chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T-cells. Using an inducible model of thymic negative selection and mRNA transcript analyses we initially identified an elevated Nfkbid expression variant as a strong candidate for an NOD Idd7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T-cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T-cells. These results indicated allelic variants of Nfkbid represent an Idd7 gene contributing to the efficiency of intrathymic deletion of diabetogenic CD8+ T-cells. However, while enhancing thymic deletion of pathogenic CD8+ T-cells, ablation of Nfkbid expression surprisingly accelerated T1D onset in NOD mice likely by numerically decreasing regulatory T- and B-lymphocytes (Tregs/Bregs), thereby reducing their peripheral immunosuppressive effects. We used microarray analysis to identify differentialy expressed genes in thymus under conditions of induced thymic negative selection. We compare two mice strains, NOD-LCMV vs NOD.Ln82-LCMV (a congenic stock for a C57BL/6 derived segment delimited by markers D7Mit117–D7Mit247).

2018-06-14 | GSE115754 | GEO

scRNA-seq and scTCR-seq of autoreactive CD8 T cells from NOD mice

Project description:Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell-mediated destruction of pancreatic β cells. Our previous work has shown that diabetogenic CD8 T cells in the islets of the non-obese diabetic (NOD) mouse model of T1D are phenotypically heterogenous, but CD8 T cell clonal heterogeneity in this model remains relatively unexplored. Here, we use paired single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of NOD mice. Clonal analysis of scTCR-seq data demonstrates that CD8 T cells targeting the immunodominant β cell epitope IGRP206-214 exhibit highly restricted TCR gene usage, with over 70% of IGRP206-214-reactive cells utilizing the same TCR V alpha, J alpha, and V beta genes. Despite this, we observe only 5% overlap of IGRP206-214-reactive CD8 T cell clones between two groups of 10 NOD mice, demonstrating the immense TCR heterogeneity generated by junctional diversity during V(D)J recombination. scRNA-seq identifies two new clusters of autoreactive CD8 T cells in the islets and six clusters of diabetogenic CD8 T cells in the spleen, including multiple memory-like clusters and a population of exhausted cells. Strong clonal overlap between IGRP206-214-reactive CD8 T cells in the islets and spleen suggests that these cells may exit the islets and enter the peripheral circulation. Finally, we identify correlations between TCR J beta gene usage, which is less restricted than that of other TCR genes, and CD8 T cell clonal expansion as well as effector fate. Collectively, our work demonstrates that IGRP206-214-specific CD8 T cells are phenotypically heterogeneous but clonally similar, raising the possibility of selectively targeting either conserved or divergent TCR structures of these cells for therapeutic benefit.

2022-06-02 | GSE200608 | GEO

RNA sequencing of CD57+ and CD57- effector memory CD8 T cells in patients with type 1 diabetes

Project description:Type 1 diabetes is an autoimmune disease in which insulin-secreting β cells of the pancreatic islets are selectively destroyed. CD8 T cells are regarded as critical players in mediating β cell destruction and as a result, considerable effort has been expended to define CD8 T cell behaviour in this disease. The overarching aim of the experiment is to characterize a recently identified autoreactive CD57-positive CD8 T cell subset which is associated with loss of function of islet beta cells in type 1 diabetes, to compare the phenotype of the CD57-positive effector memory CD8 T cells versus the CD57-negative compartment, and provide an insight into the function of these cells in the disease process. To that aim, HLA-A*24 positive patients with T1D -within 2 years of diagnosis- were asked to provide a blood, and following consent, and PBMC were isolated. CD57-positive and CD57-negative CD8 T cell populations were sorted by FACS, and finally, RNA was extracted. Amplified cDNA was obtained and used for the library preparation.

2018-08-03 | E-MTAB-6727 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data