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Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes

ABSTRACT: Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes

PROVIDER: PRJNA998046 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25408869_1.fastq.gz	Fastqsanger.gz
	SRR25408869_2.fastq.gz	Fastqsanger.gz
	SRR25408870_1.fastq.gz	Fastqsanger.gz
	SRR25408870_2.fastq.gz	Fastqsanger.gz
	SRR25408871_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes

Project description:In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD CD28-/- mice. InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, while whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

2023-07-24 | GSE238146 | GEO

Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes.

Project description:IntroductionIn spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D.MethodsTo test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice.ResultsInsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

| S-EPMC10428008 | biostudies-literature

Antigen presentation by B cells enables epitope spreading across an MHC barrier

Project description:A progressive increase in the breadth and specificity of autoantibodies over time, termed epitope spreading, drives pathogenic targeting of an ever-widening repertoire of self-components in many autoimmune diseases. Ostensibly, this progressive inclusion of additional B cell clones into an ongoing autoreactive response can occur through linked recognition, whereby proto-autoreactive B cells recognize distinct antigenic epitopes, which carry shared T cell epitopes. In a murine model displaying epitope spreading resembling that observed in systemic lupus erythematosus, we find that the epitope spreading process is compartmentalized by MHC. Antigen presentation by B cells carrying two MHC haplotypes can bridge the MHC barrier between two compartments of B cells that do not share MHC haplotypes, by communicating with two separate pools of MHC-restricted T cells. This leads to inclusion of distinct and diverse B cell reactivities in germinal centers. Our findings demonstrate a formidable capacity of B cells to drive the autoreactive response.

2022-07-01 | GSE202358 | GEO

Autoimmune peptide antigen reactivity in BXD2 mice with spontaneous systemic autoimmune disease

2015-02-28 | GSE65276 | GEO

Autoimmune peptide antigen reactivity in BXD2 mice with spontaneous systemic autoimmune disease

Project description:The aim of the study was to determine autoimmune BXD2 mouse sera reactivity to linear peptide epitopes from the Immune Epitope Database. Pooled sera from six 8-10 month old BXD2 mice was diluted at 1:1000 and incubated on a PEPperPRINT peptide microarray platform printed with peptide autoantigens. In this study, pooled sera from six 8-10 month old BXD2 mice was profiled for anti-mouse IgG (H+L) analysis of autoantibody reactivity to peptide auto-epitopes printed in duplicate on a PepperPrint Chip.

2015-02-28 | E-GEOD-65276 | biostudies-arrayexpress

Blood leukocytes recapitulate diabetogenic peptide-MHC-II complexes displayed in the pancreatic islets

Project description:Assessing the self-peptides presented by susceptible major histocompatibility complex (MHC) molecules is crucial for evaluating the pathogenesis and therapeutics of tissue-specific autoimmune diseases. However, direct examination of such MHC-bound peptides displayed in the target organ remains largely impractical. Here, we demonstrate that the blood leukocytes from non-obese diabetic (NOD) mice presented peptide epitopes to autoreactive CD4 T cells. These peptides were bound to the autoimmune class II MHC molecule, I-Ag7, and originated from insulin B-chain and C-peptide. The presentation required a glucose challenge, which stimulated the release of insulin peptides from pancreatic islets. The circulating leukocytes, especially the B cells, promptly captured and presented these peptides. Although canonical intracellular processing of insulin was involved in the presentation, extracellular binding of catabolized insulin products to I-Ag7 gave rise to a unique pathogenic epitope. Administration of monoclonal antibodies recognizing insulin B-chain abolished the presentation and diminished diabetes incidence. Mass spectrometry analysis of the leukocyte MHC-II peptidomes revealed a series of beta cell derived peptides, with identical sequences to those previously in the islet MHC-II peptidome. Thus, the WBC peptidome echoes that found in islets and serves to identify immunogenic peptides in an otherwise inaccessible tissue.

2021-03-26 | PXD024400 | Pride

The pancreatic islet MHC-II peptidome identifies key features of autoimmune peptides

Project description:The nature of autoantigens that trigger autoimmune diseases has been much discussed but direct biochemical identification is lacking for most. Addressing this question demands unbiased examination of the self-peptides displayed by a defined autoimmune MHC-II molecule. We have examined the immunopeptidome of the pancreatic islets of the NOD mouse that spontaneously develops autoimmune diabetes based on its MHC-II, the I-Ag7 variant. The relevant peptides that induced early CD4 T cells derived from insulin and C-peptide; these were also found in the MHC-II peptidome of the pancreatic lymph node and spleen. The insulin-derived peptides followed a trajectory from internal processing in beta cells to exocytosis, uptake, and presentation in islets and peripheral sites. Such process not only generated conventional epitopes but also resulted in presentation of post-translationally modified peptides, including deamidated and fused sequences. These analyses reveal the key features of a restricted component in the self-MHC-II peptidome causing autoreactivity.

2020-03-12 | PXD015408 | Pride

A deep mutational scan of the MHC class I-specific chaperone TAPBPR for sites important for peptide editing

Project description:TAP-binding protein-related (TAPBPR) is an endoplasmic reticulum-resident chaperone that facilitates class I MHC (MHC-I) processing and peptide loading. TAPBPR has (1) chaperone function to stabilize misfolded or partially folded nascent MHC-I substrates, and (2) editing function, in which it catalyzes the exchange of low affinity for high affinity antigenic peptides in the MHC-I peptide-binding groove. TAPBPR-TM is a chimera of the TAPBPR ectodomain and a canonical TM domain, which escapes the endoplasmic reticulum to reach the cell surface. We reasoned that at the cell surface, TAPBPR-TM is more likely to interact with folded MHC-I and thus surface interactions will be more representative of editing function. When tapasin, a homolog of TAPBPR and the main MHC-I-specific chaperone, is knocked out, surface trafficking of HLA-A2 (a human MHC-I allele) is severely diminished, but surface HLA-A2 levels are rescued by over-expression of TAPBPR-TM. Using this assay as the foundation for a fluorescence-based selection, we deep mutationally scanned 104 positions on TAPBPR-TM to identify sites critical for engaging folded MHC-I.

2023-03-09 | GSE218828 | GEO

Antigen presentation by B cells enables epitope spreading across an MHC barrier

Project description:Antigen presentation by B cells enables epitope spreading across an MHC barrier

| PRJNA835703 | ENA

Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire

Project description:Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire

| PRJNA1149809 | ENA

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