Abstract

We recently established that hybrid insulin peptides (HIPs), formed in islet beta-cells by fusion of insulin C-peptide fragments to peptides of Chromogranin A or Islet Amyloid Polypeptide, are ligands for diabetogenic CD4 T cell clones. The goal of this study was to investigate whether HIP-reactive T cells were indicative of ongoing autoimmunity. MHC class II tetramers were used to investigate the presence, phenotype and function of HIP-reactive and insulin-reactive T cells in non-obese diabetic (NOD) mice. Insulin-reactive T cells encounter their antigen early in disease, but they express FoxP3 and therefore may contribute to immune regulation. In contrast, HIP-reactive T cells are pro-inflammatory and highly diabetogenic in an adoptive transfer model. Because the frequency of antigen-experienced HIP-reactive T cells increases over progression of disease, they may serve as biomarkers of autoimmune diabetes.