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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autoantigens / immunology*
  • C-Peptide / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Child
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • HLA-DQ Antigens / immunology
  • HLA-DR Antigens / immunology
  • Humans
  • Insulin / immunology*
  • Insulin-Secreting Cells
  • Islets of Langerhans / cytology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Peptide Fragments / immunology*
  • Proinsulin / immunology*
  • Protein Precursors / immunology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Young Adult


  • Autoantigens
  • C-Peptide
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • Insulin
  • Peptide Fragments
  • Protein Precursors
  • Receptors, Antigen, T-Cell
  • insulin B (9-23)
  • preproinsulin
  • Proinsulin