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Proinsulin expression shapes the TCR repertoire but fails to control the development of low-avidity insulin-reactive CD8+T cells

Pearson, James A., Thayer, Terri, McLaren, James Edward, Ladell, Kristin, De Leenheer, Evy, Phillips, Amy, Davies, Joanne, Kakabadse, Dimitri, Miners, Kelly Louise, Morgan, Peter, Wen, Li, Price, David and Wong, Florence Susan 2016. Proinsulin expression shapes the TCR repertoire but fails to control the development of low-avidity insulin-reactive CD8+T cells. Diabetes 65 (6) , pp. 1679-1689. 10.2337/db15-1498

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Abstract

NOD mice, a model strain for human type 1 diabetes, express proinsulin (PI) in the thymus. However, insulin-reactive T cells escape negative selection, and subsequent activation of the CD8+ T-cell clonotype G9C8, which recognizes insulin B15-23 via an αβ T-cell receptor (TCR) incorporating TRAV8-1/TRAJ9 and TRBV19/TRBJ2-3 gene rearrangements, contributes to the development of diabetes. In this study, we used fixed TRAV8-1/TRAJ9 TCRα-chain transgenic mice to assess the impact of PI isoform expression on the insulin-reactive CD8+ T-cell repertoire. The key findings were: 1) PI2 deficiency increases the frequency of insulin B15-23–reactive TRBV19+CD8+ T cells and causes diabetes; 2) insulin B15-23–reactive TRBV19+CD8+ T cells are more abundant in the pancreatic lymph nodes of mice lacking PI1 and/or PI2; 3) overexpression of PI2 decreases TRBV19 usage in the global CD8+ T-cell compartment; 4) a biased repertoire of insulin-reactive CD8+ T cells emerges in the periphery regardless of antigen exposure; and 5) low-avidity insulin-reactive CD8+ T cells are less affected by antigen exposure in the thymus than in the periphery. These findings inform our understanding of the diabetogenic process and reveal new avenues for therapeutic exploitation in type 1 diabetes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Business (Including Economics)
Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Diabetes Association
ISSN: 0012-1797
Funders: MRC, Diabetes UK, Wellcome Trust
Date of First Compliant Deposit: 21 November 2016
Date of Acceptance: 29 February 2016
Last Modified: 28 Jun 2019 10:22
URI: http://orca.cf.ac.uk/id/eprint/96322

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