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.
journal_name
Diabetesjournal_title
Diabetesauthors
Michels AW,Landry LG,McDaniel KA,Yu L,Campbell-Thompson M,Kwok WW,Jones KL,Gottlieb PA,Kappler JW,Tang Q,Roep BO,Atkinson MA,Mathews CE,Nakayama Mdoi
10.2337/db16-1025subject
Has Abstractpub_date
2017-03-01 00:00:00pages
722-734issue
3eissn
0012-1797issn
1939-327Xpii
db16-1025journal_volume
66pub_type
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