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Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (WGBS)

ABSTRACT: The pool of beta cell-specific CD8+ T-cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell “multipotency index” and found that beta cell-specific CD8+ T-cells retained a stem-like epigenetic multipotency score. Single cell ATAC-seq analysis confirmed the co-existence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8+ T-cells. Assessment of beta cell-specific CD8+ T-cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8+ T-cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8+ T cell responses, and document the utility of this novel methylation-based multipotency index for investigating human and mouse CD8+ T-cell differentiation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE144691 | GEO | 2020/04/07

REPOSITORIES: GEO

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Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (scATAC-seq)

Project description:The pool of beta cell-specific CD8+ T-cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell “multipotency index” and found that beta cell-specific CD8+ T-cells retained a stem-like epigenetic multipotency score. Single cell ATAC-seq analysis confirmed the co-existence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8+ T-cells. Assessment of beta cell-specific CD8+ T-cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8+ T-cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8+ T cell responses, and document the utility of this novel methylation-based multipotency index for investigating human and mouse CD8+ T-cell differentiation.

2020-04-07 | GSE144692 | GEO

Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes

Project description:Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes

| PRJNA604596 | ENA

Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (WGBS)

Project description:Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (WGBS)

| PRJNA604599 | ENA

Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (scATAC-seq)

Project description:Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (scATAC-seq)

| PRJNA604598 | ENA

Mapping H3K27ac in in vitro differentiated resident memory CD8+ T cells

Project description:The networks of transcription factors (TFs) that control multipotency versus effector programs in intestinal resident memory T (TRM) cells are poorly understood. Mice with post-activation, conditional deletion of the TF Bcl11b in CD8+ T cells, infected with a food-born pathogen, had increased numbers of intestinal TRM cells, and their precursors and decreased splenic effector cells and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b-/- circulating precursors with no major alterations in their programs. Bcl11b-/- memory CD8+ T cells had an impaired recall response despite their accumulation in the gut. Intestinal Bcl11b-/- TRM cells and their precursors manifested major alterations in the residency program, with diminished expression of multipotency program genes and upregulation of the effector program genes. Integration of transcriptomics with chromatin accessibility, activating histone marks and Bcl11b genome binding showed a link between the reduction in the multipotent program genes with regions of decreased chromatin accessibility and activating histone marks in Bcl11b-/- cells. In contrast, the effector program genes displayed increased activating epigenetic status. We propose that Bcl11b regulates tissue resident TRM program genes and is positioned upstream of Tcf1 and Blimp1 in regulation of multipotency versus effector TRM program, respectively. Rescuing experiments normalized the increased numbers of intestinal Bcl11b-/- TRM cells. Thus, Bcl11b is a frontrunner in the memory tissue residency program and acts early in lineage decision, promoting TRM cell multipotency and restricting effector function.

2023-06-09 | GSE222912 | GEO

Mapping Ahr in in vitro differentiated resident memory CD8+ T cells

2023-06-09 | GSE222911 | GEO

Mapping Tcf1 in in vitro differentiated resident memory CD8+ T cells

2023-06-09 | GSE222914 | GEO

Mapping H3K4me3 in in vitro differentiated resident memory CD8+ T cells

2023-06-09 | GSE222913 | GEO

EndoC-BH1 multiomic profiling defines gene regulatory programs intrinsic to human beta cell identity and function

Project description:EndoC-BH1 is emerging as a critical human beta cell model to study the genetic and environmental etiologies of normal islet function as well as beta cell failure in diabetes. However, comprehensive knowledge of its (epi)genomic landscape has been lacking. Here, we report extensive chromosomal (spectral karyotyping), genetic (genotyping), epigenetic (ChIP-seq, ATAC-seq), chromatin interaction (Hi-C, Pol2 ChIA-PET), and transcriptomic (RNA-seq, miRNA-seq) maps of this cell model. Integrated analyses of these maps define beta cell-specific chromosome territories and transcriptional cis-regulatory programs and identify allelic effects on cis-regulatory element use and expression. Importantly, comparative analyses with maps generated in human islets/beta cells indicate substantial preservation of cis-regulatory element use and chromatin looping. Together, these maps and an interactive web application we have created for their exploration are important tools for the design and completion of experiments to probe and manipulate the genetic programs governing beta cell identity and (dys)function in diabetes.

2019-01-08 | PRJEB27824 | EVA

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

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