Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients
Open accessAbstract
A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8+ insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2–expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.
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CD8 T cells recognizing the β-cell protein IGRP represent a major pathogenic population in mice and humans.
“CD8 T cells recognizing the β-cell protein islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) represent a major pathogenic population in mice and humans6,8,10.”
From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [10]
The Results (Immunohistochemical detection; page unavailable) say IGRP reactivity was the most ubiquitous specificity in the patients’ insulitic lesions. The Discussion says these CD8 T cells may mediate β-cell loss, rather than establishing that IGRP-reactive cells are a major pathogenic population. The mouse passages describe assay optimization using NOD tissue, not the claimed pathogenic role in mice. (LLM, conf=0.86)
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- Authors
- Coppieters, K. T., Dotta, F., Amirian, N., Campbell, P. D., Kay, T. W. H., Atkinson, M. A., Roep, B. O., & von Herrath, M. G.
- Affiliations
- La Jolla Institute for Immunology (US)
- University of Siena (IT)
- St Vincent’s Institute, Fitzroy 3065, Victoria, Australia 3
- University of Florida (US)
- Leiden University Medical Center (NL)
- Type 1 Diabetes Center, the La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 1
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2012-01-02
- Volume
- 209
- Issue
- 1
- Pages
- 51-60
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3260877
- OpenAlex
- W2164707000
- Cited by
- 672
- References
- 0
- Citations by year
- 2026: 29 · 2025: 39 · 2024: 40 · 2023: 40 · 2022: 46 · 2021: 57 · 2020: 42 · 2019: 44 · 2018: 49 · 2017: 47 · 2016: 49 · 2015: 56 · 2014: 56 · 2013: 41 · 2012: 36
- FWCI
- 36.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion, cc-by-nc-sa)
- Funders
- Juvenile Diabetes Research Foundation International
- European Commission
- Ministero della Salute
- Regione Toscana
- National Institutes of Health (UL1TR000064)
- National Institute of Allergy and Infectious Diseases (R01AI092453)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- type 1 diabetes, insulitis, beta cell destruction, islet autoantigens, disease progression, HLA-A2, islet autoantibodies, gestational diabetes mellitus, type 2 diabetes
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Genes, MHC Class I, Humans, Insulin, Islets of Langerhans, Male, Autoimmunity, Gene Expression, CD8-Positive T-Lymphocytes, Young Adult
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