Cellular and Molecular Events in the Localization of Diabetogenic T Cells to Islets of Langerhans

Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1561-6. doi: 10.1073/pnas.1018973108. Epub 2011 Jan 10.

Abstract

Understanding the entry of autoreactive T cells to their target organ is important in autoimmunity because this entry initiates the inflammatory process. Here, the events that lead to specific localization of diabetogenic CD4 T cells into islets of Langerhans resulting in diabetes were examined. This was evaluated in two models, one in which T cells specific for a hen-egg white lysozyme (HEL) peptide were injected into mice expressing HEL on β cells and the other using T cells in the nonobese diabetic mouse strain, which develops spontaneous diabetes. Only T cells specific for β-cell antigens localized in islets within the first hours after their injection and were found adherent to intraislet dendritic cells (DCs). DCs surrounded blood vessels with dendrites reaching into the vessels. Localization of antigen-specific T cells did not require chemokine receptor signaling but involved class II histocompatibility and intercellular adhesion molecule 1 molecules. We found no evidence for nonspecific localization of CD4 T cells into normal noninflamed islets. Thus, the anatomy of the islet of Langerhans permits the specific localization of diabetogenic T cells at a time when there is no inflammation in the islets.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • Flow Cytometry
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / immunology
  • Intercellular Adhesion Molecule-1 / metabolism
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Fluorescence, Multiphoton
  • Muramidase / genetics
  • Muramidase / immunology
  • Muramidase / metabolism

Substances

  • Antibodies, Monoclonal
  • Histocompatibility Antigens Class II
  • Intercellular Adhesion Molecule-1
  • hen egg lysozyme
  • Muramidase