Characterization of immune cells infiltrating pancreatic islets using scRNA-seq
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE125455 | GEO | 2024/01/22
REPOSITORIES: GEO
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Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Replacing 1/5th of the HC with gluten restores high T1D to NOD mice. We hypothesized that gluten might promote inflammation in the islets. We used single cell RNA sequencing (scRNAseq) to characterize and contrast the transcriptional profiles of endocrine cells and islet infiltrating leukocytes from the pancreatic islets of Langerhans of NOD mice fed a 20% HC diet or a 16% HC + 4% gluten diet.
2023-01-04 | GSE217493 | GEO
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
Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Replacing 1/5th of the HC with gluten restores high T1D to NOD mice. We hypothesized that gluten might promote inflammation in the islets. We used TCR sequencing to characterize the clonal frequency of infiltrating T cells from the pancreatic islets of Langerhans of NOD mice fed a 20% HC diet or a 16% HC + 4% gluten diet.
2023-01-04 | GSE218336 | GEO
Project description: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.
2021-08-13 | GSE155593 | GEO
Project description:Type 1 diabetes (T1D) is an autoimmune disease triggered by T cell reactivity to protein antigens produced by the β-cells. Here we present a chronological compendium of transcriptional profiles from islets of Langerhans isolated from non-obese diabetic (NOD) mice ranging from 2 wks up to diabetes and compared to controls. Parallel analysis was made of cellular components of the islets. Myeloid cells populated the islets early during development in all mouse strains. This was followed by a type I interferon signature detectable at 4-6 wks of age only in diabetes susceptible mice. Concurrently, CD4 T cells were found within islets, many in contact with intra-islet antigen presenting cells. Early cellular signs of islet reactivity were detected by six wks. By 8 wks, NOD islets contained all major leukocytes populations and an inflammatory gene signature. This work establishes the natural transcriptional signature of T1D and provides a resource for future research. 57 RNA samples isolated from the pancreatic islets of langerhans of experimental mice: 2-18 wk old non-obese diabetic (NOD) and newly diabetic NOD were compared to controls: NOD.RAG-/-, B6.g7 and C57BL/6. There were 3 or 6 biological replicates per condition. All mice were female. All data was normalized using RMA in Arraystar. Data table includes normalized probe intensity for every probe.
2013-01-28 | E-GEOD-41203 | biostudies-arrayexpress
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 | GSE125452 | GEO
Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Exposure to HC also reduced beta-cell insulin secretion during glucose challenge suggesting that beneficial changes to beta-cell physiology might protect NOD mice from T1D. We used single cell RNA sequencing (scRNAseq) to contrast the transcriptional profiles of beta-cells and from the pancreatic islets of Langerhans of NOD mice with the scid mutation (scid mice were used to avoid confouding influence of infiltrating leukocytes) fed a 20% HC diet or a standard chow diet.
2023-01-04 | GSE217495 | GEO
Project description:Macrophages infiltrate islets early in the pathogenesis of Type 1 Diabetes (T1D), instigating islet inflammation and subsequent recognition by the adaptive immune system. A reanalysis of a publicly available single-cell RNA sequencing dataset from a pre-diabetic female non-obese diabetic (NOD) mouse revealed that the Integrated Stress Response (ISR), an evolutionarily conserved cellular pathway, is upregulated in macrophages during T1D progression. Triggered by environmental and pathological stressors, the ISR coordinates adaptive changes in gene expression to maintain cell functionality and survival and is identified as a candidate for targeted intervention. Following this, in vitro experiments on macrophage polarization and migration were conducted to evaluate changes resulting from ISR modulation. Results showed that ISR inhibition reduced the propensity of macrophages to polarize to a pro-inflammatory state without affecting anti-inflammatory polarization and reduced the migratory capabilities of pro-inflammatory macrophages. Observations from pre-diabetic female NOD mice administered ISRIB, a pharmacological ISR inhibitor, indicated a reduction in macrophage numbers within the islets, with increased PD-L1 expression on the macrophages.
2024-10-28 | GSE278047 | GEO
Project description:Background: Activation of stress pathways intrinsic to the β cell are thought to both accelerate β cell death and increase β cell immunogenicity in type 1 diabetes (T1D). However, information on the timing and scope of these responses is lacking. Methods: To identify temporal and disease-related changes in islet β cell protein expression, SWATH-MS/MS proteomics analysis was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in the maintenance of β cell function and stress mitigation, followed by loss of expression of protective proteins that heralded diabetes onset. Pathway analysis identified EIF2 signaling and the unfolded protein response, mTOR signaling, mitochondrial function, and oxidative phosphorylation as commonly modulated pathways in both diabetic NOD mice and NOD-SCID mice rendered acutely diabetic by adoptive transfer, highlighting this core set of pathways in T1D pathogenesis. In immunofluorescence validation studies, β cell expression of protein disulfide isomerase A1 (PDIA1) and 14-3-3b were found to be increased during disease progression in NOD islets, while PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to age and sex-matched non-diabetic controls. Interpretation: We identified a common and core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D.
2023-03-11 | PXD035504 | Pride
Project description:Our current understanding of the pathogenesis of T1D arose in large part from studies using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Of concern, therapeutic interventions shown to significantly dampen or even reverse disease in mouse models have not successfully translated into interventions in human T1D. The present study addresses this disconnect in research translation by directly analyzing human donor islets from individuals with T1D, aiming to provide insight into disease mechanisms and identify potential target pathways for therapeutic intervention. We obtained human islets from a young individual with short-duration T1D, an older individual with long-duration T1D and three non-diabetic donors, and performed unbiased functional genomic analysis by high depth RNA sequencing on these unique cases. This analysis identified several inflammatory pathways upregulated in short-duration disease, which surprisingly included many components of innate immunity. Subsequent manipulation of one of these pathways/factors in NOD mice resulted in a significant reduction in diabetes progression when inhibition occurred early in disease progression. Taken together our data demonstrates that the direct analysis of human islets is essential for identifying relevant and promising novel targets for translation into effective therapeutic interventions for human T1D.
2018-07-30 | GSE102371 | GEO