Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response

Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1567-72. doi: 10.1073/pnas.1018975108. Epub 2011 Jan 10.

Abstract

In an accompanying paper, we find specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intraislet dendritic cells bearing the β-cell-peptide-MHC complex. Here, we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. Vascular cell adhesion molecule-1 (VCAM-1) expression was notable in blood vessels, as was intercellular adhesion molecule-1 (ICAM-1). ICAM-1 was also found on β-cells. These expression changes induced the entry of nonspecific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of nonspecific T cells required a chemokine response and VCAM-1 expression by the islets. IFN-γ was important for the early gene expression changes in the islets. By microarray analysis, we detected up-regulation of a group of IFN-inducible genes as early as 8 h post-T-cell transfer. These studies establish that entry of diabetogenic T cells induces a state of receptivity of islets to subsequent immunological insults.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Blood Vessels / metabolism
  • 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
  • Flow Cytometry
  • Gene Amplification
  • Gene Expression Profiling
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Homeodomain Proteins / metabolism
  • Intercellular Adhesion Molecule-1 / genetics
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Islets of Langerhans / blood supply
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Muramidase / genetics
  • Muramidase / immunology
  • Muramidase / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Receptors, Interferon / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Vascular Cell Adhesion Molecule-1 / genetics

Substances

  • Homeodomain Proteins
  • Receptors, Interferon
  • Vascular Cell Adhesion Molecule-1
  • interferon gamma receptor
  • Intercellular Adhesion Molecule-1
  • RAG-1 protein
  • Interferon-gamma
  • hen egg lysozyme
  • Muramidase

Associated data

  • GEO/GSE26147