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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Blood Vessels / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / transplantation
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / metabolism
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Flow Cytometry
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Gene Amplification
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Gene Expression Profiling
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Homeodomain Proteins / genetics
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Homeodomain Proteins / immunology
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Homeodomain Proteins / metabolism
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Intercellular Adhesion Molecule-1 / genetics
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Interferon gamma Receptor
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Islets of Langerhans / blood supply
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Islets of Langerhans / immunology*
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Islets of Langerhans / metabolism*
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, Transgenic
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Muramidase / genetics
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Muramidase / immunology
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Muramidase / metabolism
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Oligonucleotide Array Sequence Analysis
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Receptors, Interferon / genetics
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Receptors, Interferon / immunology
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Receptors, Interferon / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology
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Vascular Cell Adhesion Molecule-1 / genetics
Substances
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Homeodomain Proteins
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Receptors, Interferon
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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RAG-1 protein
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Interferon-gamma
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hen egg lysozyme
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Muramidase