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

AW Michels, LG Landry, KA McDaniel, L Yu… - Diabetes, 2017 - Am Diabetes Assoc
AW Michels, LG Landry, KA McDaniel, L Yu, M Campbell-Thompson, WW Kwok, KL Jones…
Diabetes, 2017Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc