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Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes.

Citation
Michels, A. W., et al. “Islet-Derived Cd4 T Cells Targeting Proinsulin In Human Autoimmune Diabetes.”. Diabetes, pp. 722-734.
Center University of Washington University of Colorado Denver
Multicenter
Multicenter
Author Aaron W Michels, Laurie G Landry, Kristen A McDaniel, Liping Yu, Martha Campbell-Thompson, William W Kwok, Kenneth L Jones, Peter A Gottlieb, John W Kappler, Qizhi Tang, Bart O Roep, Mark A Atkinson, Clayton E Mathews, Maki Nakayama
Abstract

Type 1 diabetes results from chronic autoimmune destruction of insulin-producing β-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.

Year of Publication
2017
Journal
Diabetes
Volume
66
Issue
3
Number of Pages
722-734
Date Published
12/2017
ISSN Number
1939-327X
DOI
10.2337/db16-1025
Alternate Journal
Diabetes
PMID
27920090
PMCID
PMC5319719
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