Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):4429-34. doi: 10.1073/pnas.1502967112. Epub 2015 Mar 23.


Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset.

Keywords: CD4 T cells; autoimmunity; diabetes; insulin; self-tolerance.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Autoantibodies / metabolism
  • CD4-Positive T-Lymphocytes / metabolism*
  • Child
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / metabolism*
  • Female
  • Genotype
  • HLA-DQ Antigens / genetics
  • Humans
  • Inflammation / metabolism*
  • Insulin / genetics*
  • Insulin / metabolism*
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Receptors, Antigen, T-Cell / metabolism
  • Sequence Homology, Amino Acid
  • Young Adult


  • Autoantibodies
  • Cytokines
  • HLA-DQ Antigens
  • Insulin
  • Receptors, Antigen, T-Cell
  • Interleukin-10
  • Interferon-gamma