Cited by 195Diabetes and associated disordersT-cell and B-cell ImmunologyPancreatic function and diabetes

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Regulatory T cell dysfunction in type 1 diabetes: what's broken and how can we fix it?

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Hull, Caroline M., Peakman, Mark, Tree, Timothy I. M.·2017·Diabetologia

DOI 10.1007/s00125-017-4377-1PMC PMC6448885

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Abstract

Type 1 diabetes is an autoimmune disease characterised by the destruction of insulin producing beta cells in the pancreas. Whilst it remains unclear what the original triggering factors for this destruction are, observations from the natural history of human type 1 diabetes, including incidence rates in twins, suggest that the disease results from a combination of genetic and environmental factors. Whilst many different immune cells have been implicated, including members of the innate and adaptive immune systems, a view has emerged over the past 10 years that beta cell damage is mediated by the combined actions of CD4 + and CD8 + T cells with specificity for islet autoantigens. In health, these potentially pathogenic T cells are held in check by multiple regulatory mechanisms, known collectively as ‘immunological tolerance’. This raises the question as to whether type 1 diabetes develops, at least in part, as a result of a defect in one or more of these control mechanisms. Immunological tolerance includes both central mechanisms (purging of the T cell repertoire of high-affinity autoreactive T cells in the thymus) and peripheral mechanisms, a major component of which is the action of a specialised subpopulation of T cells, known as regulatory T cells (Tregs). In this review, we highlight the evidence suggesting that a reduction in the functional capacity of different Treg populations contributes to disease development in type 1 diabetes. We also address current controversies regarding the putative causes of this defect and discuss strategies to correct it as a means to reduce or prevent islet destruction in a clinical setting.

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Fig. 1 Alterations in Treg phenotype and function observed in type 1 diabetes. FOXP3+ Tregs from individuals with type 1 diabetes are less able to control the proliferation of and cytokine production by effector CD4+ T cells compared with those from individuals without diabetes. This defective regulation may be owing to two non-mutually exclusive factors: differences in the Teff population (shown in red boxes) and/or Treg intrinsic defects (shown in blue boxes) (where differences overlap, details are shown in red/blue boxes). Additionally, the frequency and function of induced Tregs (iTregs) may play a role in promoting imbalance of the immune system in type 1 diabetes (green boxes). In many cases, these immunophenotypes may be influenced by gene polymorphisms associated with type 1 diabetes susceptibility (shown in grey boxes). Potential avenues for strengthening immune regulation by Treg invigoration are indicated in beige boxes. Red circles, IFN-γ/IL-17; green circles, IL-10. The grey arrow represents how unstable expression profiles of FOXP3 by Tregs increases the production of proinflammatory cytokines, promoting the function and expansion of islet-destructive Teff cells. MHC-CII, HLA-DRB1/HLA-DQA1/HLA-DQB1; STAT, signal transducer and activator of transcription; Th, T helperCC BY · PubMed Central

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Authors: Hull, C. M., Peakman, M., & Tree, T. I. M.
Affiliations: Guy's Hospital (GB)
Corresponding author: Hull, Caroline M.
Tree, Timothy I. M.
ORCID: Hull, Caroline M.
Peakman, Mark
Tree, Timothy I. M.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2017-08-02
Volume: 60
Issue: 10
Pages: 1839-1850
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-017-4377-1
PMC: PMC6448885
OpenAlex: W2739639576
Cited by: 194
References: 109
Citations by year: 2026: 11 · 2025: 32 · 2024: 30 · 2023: 17 · 2022: 25 · 2021: 25 · 2020: 21 · 2019: 19 · 2018: 13 · 2017: 1
FWCI: 1.89
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: Diabetologia (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Research Portal (King's College London) (publishedVersion, cc-by)
Funders: King's College London
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 › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Keywords: type 1 diabetes, regulatory T cells, immune tolerance, beta cell destruction, islet autoantigens, CD4+ T cells, CD8+ T cells, thymic selection, peripheral tolerance, Treg dysfunction, Treg therapy, autoimmunity
MeSH terms: Animals, Diabetes Mellitus, Type 1, Humans, Immune Tolerance, T-Lymphocytes, Regulatory

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Regulatory T cell dysfunction in type 1 diabetes: what's broken and how can we fix it?

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