T-cell responses to hybrid insulin peptides prior to type 1 diabetes development

Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2019129118. doi: 10.1073/pnas.2019129118.


T-cell responses to posttranslationally modified self-antigens are associated with many autoimmune disorders. In type 1 diabetes, hybrid insulin peptides (HIPs) are implicated in the T-cell-mediated destruction of insulin-producing β-cells within pancreatic islets. The natural history of the disease is such that it allows for the study of T-cell reactivity prior to the onset of clinical symptoms. We hypothesized that CD4 T-cell responses to posttranslationally modified islet peptides precedes diabetes onset. In a cohort of genetically at-risk individuals, we measured longitudinal T-cell responses to native insulin and hybrid insulin peptides. Both proinflammatory (interferon-γ) and antiinflammatory (interluekin-10) cytokine responses to HIPs were more robust than those to native peptides, and the ratio of such responses oscillated between pro- and antiinflammatory over time. However, individuals who developed islet autoantibodies or progressed to clinical type 1 diabetes had predominantly inflammatory T-cell responses to HIPs. Additionally, several HIP T-cell responses correlated to worsening measurements of blood glucose, highlighting the relevance of T-cell responses to posttranslationally modified peptides prior to autoimmune disease development.

Keywords: T cell; antigen; autoimmunity; posttranslational modification; type 1 diabetes.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies / genetics
  • Autoantibodies / immunology
  • Autoantigens / genetics*
  • Autoantigens / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Child
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Progression
  • Female
  • Humans
  • Insulin / genetics
  • Insulin / immunology*
  • Insulin-Secreting Cells / immunology
  • Interferon-gamma / genetics*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / pathology
  • Male
  • Peptides / genetics*
  • Peptides / immunology
  • T-Lymphocytes / immunology
  • Young Adult


  • Autoantibodies
  • Autoantigens
  • IFNG protein, human
  • Insulin
  • Peptides
  • Interferon-gamma