期刊
DIABETES
卷 66, 期 3, 页码 722-734出版社
AMER DIABETES ASSOC
DOI: 10.2337/db16-1025
关键词
-
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-099317, DK-095995, DK-057516, DK-104194, DK-104223, DK-101120, DK-104155, DK-08231, DK-110845]
- National Institutes of Health [P30CA046934, P01A142288]
- JDRF [25-2010-624, 1-INO-2014-173-A-V, 25-2013-268, 17-2012-3, 25-2012]
- Children's Diabetes Foundation
- Peter Culshaw Family Award
- Colorado Clinical and Translational Sciences Institute [TR001082]
Type 1 diabetes results from chronic autoimmune destruction of insulin-producing beta-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 longterm 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.
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