ArticleThe Journal of clinical investigation2008
CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope.
Article in The Journal of clinical investigation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 247 papers.
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Who cites it
247 citing papers in PubMed.
- Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes.The Journal of clinical investigation · 2018Trial
- High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.Journal of immunology (Baltimore, Md. : 1950) · 2014Trial
- Immune therapy and β-cell death in type 1 diabetes.Diabetes · 2013Trial
- Multiomics approaches reveal direct NF-κB p65 target genes in pancreatic islets during cytokine exposure and in type 1 diabetes.American journal of physiology. Endocrinology and metabolism · 2026Article
- From Disposal to Display: Crinophagy as a β-Cell Source of Neoantigens in Type 1 Diabetes.Immunological reviews · 2026Review
- Beyond Sequence: Posttranslational Remodeling of Antigens in Autoimmunity.Immunological reviews · 2026Review
- Beta cell reactivity defines disease-relevant pancreatic CD8 T cells in type 1 diabetes.bioRxiv : the preprint server for biology · 2026Article
- A universal platform for simultaneous TCRα/β removal enables safer and more potent TCR therapies and autoimmune modeling.bioRxiv : the preprint server for biology · 2026Article
- Extracellular vesicles from cytokine-treated human pancreatic ductal cells enhance HLA class I expression in beta cells.Frontiers in immunology · 2026Article
- Is the NOD mouse a good model for type 1 diabetes?Diabetologia · 2026Review
- Proteogenomic Discovery of Novel Open Reading Frames With HLA Immune Presentation on Human β-Cells.Diabetes · 2025Article
- Lnk/Sh2b3 regulates initiation and severity of autoimmune insulitis and contributes to diabetes risk.Life science alliance · 2025Article
- TCR-Based Antigen-Specific Therapy for Type 1 Diabetes Mellitus: From Editing Autoreactive Clones to Tolerance Induction.International journal of molecular sciences · 2025Review
- Human stem cell-derived β cells expressing an optimized CD155 reduce cytotoxic immune cell function for application in type 1 diabetes.Science advances · 2025Article
- Unraveling Type 1 Diabetes: Integrating Microbiome, Metabolomics, and Immunomodulation for Next-Generation Therapies.International journal of molecular sciences · 2025Review
- Molecular and Inflammatory Etiologies of β-Cell Dysfunction in Type 1 Diabetes.Physiology (Bethesda, Md.) · 2025Review
- Article
- Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.EBioMedicine · 2025Article
- Article
- Review
187 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issuedUnger, Wendy [corrected to Unger, Wendy W]
Authors and funding
19 authors.
Funding
Abstract
The final pathway of beta cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill beta cells via recognition of a glucose-regulated epitope. First, we identified 2 naturally processed epitopes from the human preproinsulin signal peptide by elution from HLA-A2 (specifically, the protein encoded by the A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8+ T cells from HLA-A2+ patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide-specific CD8+ T cells killed human beta cells in vitro. Critically, at high glucose concentration, beta cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human beta cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing beta cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining beta cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.