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?-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.

ABSTRACT: Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet ?-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I tetramer staining to quantify and characterize ?-cell-specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarkably, we found that ?-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy control subjects, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the ?-cell-specific CD8 T cell compartment. Molecular analysis of selected ?-cell-specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor repertoires comprising exclusively private clonotypes. Collectively, these data identify novel and distinctive features of disease-relevant CD8 T cells that inform the immunopathogenesis of type 1 diabetes.

SUBMITTER: Skowera A

PROVIDER: S-EPMC4557541 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.

Skowera Ania A Ladell Kristin K McLaren James E JE Dolton Garry G Matthews Katherine K KK Gostick Emma E Kronenberg-Versteeg Deborah D Eichmann Martin M Knight Robin R RR Heck Susanne S Powrie Jake J Bingley Polly J PJ Dayan Colin M CM Miles John J JJ Sewell Andrew K AK Price David A DA Peakman Mark M

Diabetes 20140923 3

Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I tetramer staining to quantify and characterize β-cell-specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarka ...[more]

PMID: 25249579

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Project description:AimProteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples.MethodsBeta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible.ResultsTwenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p ≤ 0.01). Receiver operator characteristic curves determined the protein panels to have excellent discrimination between low and high beta-cell function. Linear regression analysis determined that beta-endorphin and IL-17F have strong associations with beta-cell function/HOMA-IR, β = 0.039 (p = 0.005) and β = -0.027 (p = 0.013) respectively. Calcineurin and CRTAM were strongly associated with the disposition index (β = 0.005 and β = 0.005 respectively, p = 0.012). In vitro experiments confirmed that IL-17F modulated insulin secretion in the BRIN-BD11 cell line, with the lower concentration of 10 ng/mL significantly increasing glucose stimulated insulin secretion (p = 0.043).ConclusionsEarly detection of compromised beta-cell function could allow for implementation of nutritional and lifestyle interventions before progression to type 2 diabetes.

Dataset Information

?-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.

Publications

β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.

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