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Islet-derived CD4 T-cells targeting proinsulin in human autoimmune diabetes

, : Islet-derived CD4 T-cells targeting proinsulin in human autoimmune diabetes. Diabetes (): -

NlmCategory="UNASSIGNED">Type 1 diabetes results from chronic autoimmune destruction of insulin-producing beta cells within pancreatic islets. While 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 type 1 diabetes patients. We identified hundreds of T-cells from inflamed pancreatic islets of three young type 1 diabetes organ donors 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 -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 is 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, while 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

DOI: 10.2337/db16-1025

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