Title

Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells.

Document Type

Article

Publication Date

2003

Keywords

CD8-Positive-T-Lymphocytes, Cell-Adhesion, Cells-Cultured, Chemotaxis, Diabetes-Mellitus-Experimental, Endothelium-Vascular, Female, Genes-MHC-Class-I, Insulin, Islets-of-Langerhans, Major-Histocompatibility-Complex, Male, Mice, Mice-Inbred-Strains, Monosaccharide-Transport-Proteins, Pancreas, Peptides, Pertussis-Toxin, Receptors-Antigen-T-Cell, Receptors-Chemokine, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Tissue-Culture, Vascular-Cell-Adhesion-Molecule-1

JAX Source

J Exp Med 2003 Mar; 197(5):643-56.

Abstract

Activated insulin-specific CD8(+) T cells (IS-CD8(+) cells) home to the pancreas, destroy beta cells, and cause rapid diabetes upon transfer into diabetes-prone NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free of preexistent inflammation. Thus, we hypothesized that islet-specific homing may be in part dependent on IS-CD8(+) cells' recognition of the cognate major histocompatibility complex (MHC)/peptide complexes presented by pancreatic endothelial cells, which acquire the antigen (insulin) from beta cells. In fact, islet-specific homing was abrogated in mice that lack MHC class I expression, or presentation of the specific peptide, or have impaired insulin secretion. Moreover, we found that IS-CD8(+) cells directly recognized pancreatic endothelial cells in islet organ cultures. Triggering of IS-CD8(+) cells' T cell receptor (TCR) led to activation of integrins expressed by these cells. In addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8(+) cells' adhesion to endothelial monolayers and for successful homing in vivo. Thus, signaling through TCR and chemokine receptors work in concert to assure firm adhesion of T cells to the pancreatic endothelium. The antigen cross-presentation ability of endothelia may therefore contribute to the specificity of homing of activated T lymphocytes to the tissues where antigens are generated by other cell types.