Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion

J Exp Med. 2011 Nov 21;208(12):2375-83. doi: 10.1084/jem.20111502. Epub 2011 Nov 7.


In nonobese diabetic (NOD) mice, two sets of autoreactive CD4(+) T cells recognize the B:9-23 segment of the insulin B chain. One set, type A, recognizes insulin presented by antigen-presenting cells (APCs). These T cells are highly deleted in the thymus. The second set, type B, does not recognize insulin protein but reacts with soluble B chain peptide. This set is not deleted in the thymus but is activated in the islets of Langerhans. In this study, we examine the specificity of these two types of T cells. The protein-reactive set recognizes the stretch of residues 13-21 of the insulin B chain. The set reactive to peptide only recognizes the stretch from residues 12-20. A single amino acid shift of the B chain peptide bound to I-A(g7) determines whether T cells recognize peptides generated by the processing of insulin, and consequently their escape from thymic purging. Biochemical experiments indicate that peptides bound in the 13-21 register interact more favorably with I-A(g7) than peptides that bind in the 12-20 register. Thus, self-reactive T cells can become pathogenic in the target organ where high concentrations of antigen and/or differences in intracellular processing present peptides in registers distinct from those found in the thymus.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Autoimmunity / immunology*
  • CD4-Positive T-Lymphocytes / cytology*
  • Cell Line
  • DNA Primers / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Enzyme-Linked Immunospot Assay
  • Insulin / genetics
  • Insulin / immunology*
  • Insulin / metabolism
  • Islets of Langerhans / immunology*
  • Major Histocompatibility Complex / immunology*
  • Mice
  • Mice, Inbred NOD
  • Protein Binding
  • T-Cell Antigen Receptor Specificity
  • Thymus Gland / immunology


  • DNA Primers
  • Insulin