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Diabetes. 2017 Mar;66(3):722-734. doi: 10.2337/db16-1025. Epub 2016 Dec 5.

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

Author information

1
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
2
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
3
Benaroya Research Institute at Virginia Mason, Seattle, WA.
4
Department of Medicine, University of Washington, Seattle, WA.
5
Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado School of Medicine, Aurora, CO.
6
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
7
Howard Hughes Medical Institute, Denver, CO.
8
Department of Biomedical Research, National Jewish Health, Denver, CO.
9
Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO.
10
Department of Surgery, University of California, San Francisco, San Francisco, CA.
11
Diabetes Center, University of California, San Francisco, San Francisco, CA.
12
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
13
Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA.
14
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO maki.nakayama@ucdenver.edu.

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.

PMID:
27920090
PMCID:
PMC5319719
DOI:
10.2337/db16-1025
[Indexed for MEDLINE]
Free PMC Article

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