University of Oulu

Yeo, L., Pujol‐Autonell, I., Baptista, R., Eichmann, M., Kronenberg‐Versteeg, D., Heck, S., Dolton, G., Sewell, A.K., Härkönen, T., Mikk, M.‐L., Toppari, J., Veijola, R., Knip, M., Ilonen, J. and Peakman, M. (2020), Circulating β cell‐specific CD8+ T cells restricted by high‐risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes. Clin Exp Immunol, 199: 263-277. doi:10.1111/cei.13391

Circulating β cell‐specific CD8⁺ T cells restricted by high‐risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

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Author: Yeo, L.1,2; Pujol‐Autonell, I.1; Baptista, R.2;
Organizations: 1Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College London, London, UK
2National Institute of Health Research Biomedical Research Centre at Guy’s and St Thomas’ Hospital and King’s College London, London, UK
3Division of Infection and Immunity, School of Medicine and Systems Immunity Research Institute, Cardiff University, Cardiff, UK
4Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
5Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
6Department of Paediatrics, University of Turku and Turku University Hospital, Turku, Finland
7Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
8Department of Paediatrics, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
9Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
10Department of Pediatrics, Tampere University Hospital, Tampere, Finland
11Folkhälsan Research Centre, Helsinki, Finland
12Clinical Microbiology, Turku University Hospital, Turku, Finland
13King’s Health Partners Institute of Diabetes, Endocrinology and Obesity, London, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
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Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2020-05-14


In type 1 diabetes (T1D), autoreactive cytotoxic CD8⁺ T cells are implicated in the destruction of insulin‐producing β cells. The HLA‐B*3906 and HLA‐A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8⁺ T cells that recognize peptides presented by these class I molecules on pancreatic β cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)‐specific and insulin B (InsB)‐specific CD8⁺ cells in HLA‐B*3906⁺ children newly diagnosed with T1D and in high‐risk HLA‐A*2402⁺ children before the appearance of disease‐specific autoantibodies and before diagnosis of T1D. Antigen‐specific CD8+ T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA‐B*3906⁺ children with T1D, we observed an increase in PPI5–12‐specific transitional memory CD8⁺ T cells compared to non‐diabetic, age‐ and HLA‐matched subjects. Furthermore, PPI5–12‐specific CD8⁺ T cells in HLA‐B*3906⁺ children with T1D showed a significantly more antigen‐experienced phenotype compared to polyclonal CD8⁺ T cells. In longitudinal samples from high‐risk HLA‐A*2402⁺ children, the percentage of terminal effector cells within the InsB15–24‐specific CD8⁺ T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA‐B*3906‐restricted autoreactive CD8⁺ T cells in T1D. Collectively, our results provide evidence that β cell‐reactive CD8⁺ T cells restricted by disease‐associated HLA class I molecules display an antigen‐experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.

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Series: Clinical & experimental immunology
ISSN: 0009-9104
ISSN-E: 1365-2249
ISSN-L: 0009-9104
Volume: 199
Issue: 3
Pages: 263 - 277
DOI: 10.1111/cei.13391
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3123 Gynaecology and paediatrics
Funding: This work was supported by the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre Award to Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London and the Juvenile Diabetes Research Foundation (JDRF) award, ‘Immunological markers of beta cell decline in new onset type 1 diabetes’ (17‐2013‐583). Support from the Innovative Medicines Initiative‐2 Joint Undertaking under grant agreement no. 115797 INNODIA, which receives support from the European Union’s Horizon 2020 research and Innovation Programme and EFPIA, JDRF International and The Leona M. and Harry B. Helmsley Charitable Trust to MP is also acknowledged. IPA is in receipt of a Marie Skłodowska‐Curie Individual Fellowship (Grant Agreement no. 704974). A. K. S. is a Wellcome Senior Investigator (WT100327MA). JDRF, the Academy of Finland and Sigrid Jusélius Foundation have supported the DIPP study and the Finnish Pediatric Diabetes Register. The contents of this article are solely the responsibility of the authors.
EU Grant Number: (115797) INNODIA - Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797
Copyright information: © 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.