Pathogenic CD4⁺ T cells recognizing an unstable peptide of insulin are directly recruited into islets bypassing local lymph nodes

J Exp Med. 2013 Oct 21;210(11):2403-14. doi: 10.1084/jem.20130582. Epub 2013 Oct 14.

Abstract

In the nonobese diabetic mouse, a predominant component of the autoreactive CD4(+) T cell repertoire is directed against the B:9-23 segment of the insulin B chain. Previous studies established that the majority of insulin-reactive T cells specifically recognize a weak peptide-MHC binding register within the B:9-23 segment, that to the 12-20 register. These T cells are uniquely stimulated when the B:9-23 peptide, but not the insulin protein, is offered to antigen presenting cells (APCs). Here, we report on a T cell receptor (TCR) transgenic mouse (8F10) that offers important new insights into the biology of these unconventional T cells. Many of the 8F10 CD4(+) T cells escaped negative selection and were highly pathogenic. The T cells were directly recruited into islets of Langerhans, where they established contact with resident intra-islet APCs. Immunogenic insulin had to be presented in order for the T cells to localize and cause disease. These T cells bypassed an initial priming stage in the pancreatic lymph node thought to precede islet T cell entry. 8F10 T cells induced the production of antiinsulin antibodies and islets contained immunoglobulin (IgG) deposited on β cells and along the vessel walls.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD4-Positive T-Lymphocytes / pathology*
  • Female
  • Insulin / chemistry
  • Insulin / immunology*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / pathology*
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / immunology*
  • Protein Stability
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • Insulin
  • Peptides
  • Receptors, Antigen, T-Cell