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. (10th November 2019)

• Record Type: Journal Article
• Authors: 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; Peakman, M
• Is Part Of: Clinical and experimental immunology. Volume 199:Number 3(2020)
• Page Start: 263
• Page End: 277
• Publication Date: 2019-11-10
• Subjects: CD8+ T cells -- HLA-B*39 -- HLA-A*24 -- type 1 diabetes; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.13391
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: 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 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. Graphical Abstract: