Circulating beta 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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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 2020 , ' Circulating beta 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 ' , Clinical and Experimental Immunology , vol. 199 , no. 3 , pp. 263-277 . https://doi.org/10.1111/cei.13391

Title: Circulating beta 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
Author: 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.
Contributor: University of Helsinki, HUS Children and Adolescents
University of Helsinki, HUS Children and Adolescents
Date: 2020-03
Language: eng
Number of pages: 15
Belongs to series: Clinical and Experimental Immunology
ISSN: 0009-9104
URI: http://hdl.handle.net/10138/313390
Abstract: In type 1 diabetes (T1D), autoreactive cytotoxic CD8(+) T cells are implicated in the destruction of insulin-producing beta 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 beta 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 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 beta 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.
Subject: CD8(+) T cells
HLA-B*39
HLA-A*24
type 1 diabetes
GLUTAMIC-ACID DECARBOXYLASE
PREPROINSULIN SIGNAL PEPTIDE
ZINC TRANSPORTER 8
GENETIC SUSCEPTIBILITY
ISLET ANTIGEN-2
IMMUNE-RESPONSE
YOUNG-CHILDREN
CUTTING EDGE
DOUBLE-BLIND
MEMORY
3121 General medicine, internal medicine and other clinical medicine
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