Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors

Front Endocrinol (Lausanne). 2021 Mar 25:12:622647. doi: 10.3389/fendo.2021.622647. eCollection 2021.


Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.

Keywords: T cell receptors; antigens; epitopes; islets; preproinsulin; type 1 diabetes.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • Diabetes Mellitus, Type 1 / metabolism*
  • Epitopes / metabolism
  • Humans
  • Insulin / pharmacology*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Protein Precursors / pharmacology*
  • Tissue Donors


  • Epitopes
  • Insulin
  • Protein Precursors
  • preproinsulin