King's College London

Research portal

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

Research output: Contribution to journalArticle

Lorraine Yeo, Irma Pujol-Autonell, Roman Baptista, Martin Eichmann, Deborah Kronenberg-Versteeg, Susanne Heck, Garry Dolton, Andrew K Sewell, Taina Härkönen, Mari-Liis Mikk, Jorma Toppari, Riitta Veijola, Mikael Knip, Jorma Ilonen, Mark Peakman

Original languageEnglish
JournalClinical and Experimental Immunology
DOIs
Publication statusE-pub ahead of print - 29 Oct 2019

Bibliographical note

© 2019 British Society for Immunology.

King's Authors

Abstract

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 + T 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 PPI 5–12-specific transitional memory CD8 + T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI 5–12-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 InsB 15–24-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.

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454