CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope

J Autoimmun. 2008 Aug;31(1):30-41. doi: 10.1016/j.jaut.2008.02.001. Epub 2008 Apr 2.


Recent studies suggest that insulin is a primary autoantigen for type 1 diabetes. Several studies have identified preproinsulin (PPI) 76-90 as an immunodominant CD4+ T cell epitope. We developed a class II tetramer reagent using a modified PPI peptide with a lysine to serine substitution at position 88 (PPI 78-90(88S)) that has high binding affinity to DRA1*0101/DRB1*0401 (DR0401). Using this tetramer, positive responses were observed from both DR0401 healthy and type 1 diabetic subjects when T cells were stimulated with the PPI 78-90(88S) peptide. Seventy percent of these T cells proliferated in response to both the wild type PPI 76-90 and PPI 78-90(88S) peptides. However, when T cells were stimulated with wild type peptide and assayed with DR0401/PPI 78-90(88S), positive responses were only detected in the diabetic group but not in healthy subjects. When highly purified CD4+CD25-CD45RA+ T cells were stimulated with PPI 78-90(88S) peptide in the absence of antigen-presenting cells, T cells from the diabetic group were able to respond to peptide stimulation, while T cells from healthy subjects were not. These data suggest that T cells from type 1 diabetic subjects have a lower threshold of activation in response to PPI peptide stimulation as compared to healthy subjects.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Proliferation / drug effects
  • Cell Separation
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • Flow Cytometry
  • HLA-DR Antigens / chemistry
  • HLA-DR Antigens / immunology*
  • HLA-DRB1 Chains
  • Humans
  • Insulin / chemistry
  • Insulin / immunology*
  • Insulin / pharmacology
  • Leukocyte Common Antigens / immunology
  • Leukocyte Common Antigens / metabolism
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Protein Interaction Domains and Motifs / immunology
  • Protein Precursors / chemistry
  • Protein Precursors / immunology*
  • Protein Precursors / pharmacology


  • Epitopes, T-Lymphocyte
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • Insulin
  • Protein Precursors
  • preproinsulin
  • Leukocyte Common Antigens