ArticleThe Journal of experimental medicine2021
A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance.
Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 55 citations in OpenAlex.
- Exploration of common genomic signatures of systemic juvenile rheumatoid arthritis and type 1 diabetes.Scientific reports · 2023Pooled it
- Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function.JCI insight · 2026Article
- Gain-of-function mutation inbioRxiv : the preprint server for biology · 2026Article
- Unraveling the Systems Biology of Curcumin: A Mini-review of its Anti-diabetic Potential through Network Pharmacology.Cell biochemistry and biophysics · 2026Review
- STAT3 SH2 Domain Aspartic Acid 661 Mutations Activate Immune Gene Programs.Journal of cellular and molecular medicine · 2026Article
- A case report of ADMIO type 1 caused by aFrontiers in immunology · 2026Article
- STAT3 axis in cancer and cancer stem cells: From oncogenesis to targeted therapies.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- Current trends in single-cell RNA sequencing applications in diabetes mellitus.FEBS open bio · 2025Review
- A realistic FastQ-based framework FastQDesign for ScRNA-seq study design issues.Communications biology · 2025Article
- The immune tolerance role of Bregs in inhibiting human inflammatory diseases, with a focus on diabetes mellitus.Frontiers in immunology · 2025Review
- A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice.The Journal of experimental medicine · 2024Article
- Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.Science translational medicine · 2024Article
- STAT5B SH2 variants disrupt mammary enhancers and the stability of genetic programs during pregnancy.bioRxiv : the preprint server for biology · 2024Article
- Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection.Frontiers in endocrinology · 2024Review
- Signal Transducer and Activator of Transcription Proteins at the Nexus of Immunodeficiency, Autoimmunity and Cancer.Biomedicines · 2023Review
- Deletion of Vβ3Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Th2 cell clonal expansion at diagnosis in human type 1 diabetes.Clinical immunology (Orlando, Fla.) · 2023Article
- Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.Cell & bioscience · 2023Review
- Deficiencies and Dysregulation of STAT Pathways That Drive Inborn Errors of Immunity: Lessons from Patients and Mouse Models of Disease.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- The ups and downs of STAT3 function: too much, too little and human immune dysregulation.Clinical and experimental immunology · 2023Review
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
Naturally occurring cases of monogenic type 1 diabetes (T1D) help establish direct mechanisms driving this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator STAT3 was found to cause neonatal T1D. We engineered a novel knock-in mouse incorporating this highly diabetogenic human STAT3 mutation (K392R) and found that these mice recapitulated the human autoimmune diabetes phenotype. Paired single-cell TCR and RNA sequencing revealed that STAT3-GOF drives proliferation and clonal expansion of effector CD8+ cells that resist terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and have differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed a CD8+ cell reacting against known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ cells is sufficient to accelerate diabetes onset. Altogether, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis.
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Registered trials
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