Presentation of Antigen by Endothelial Cells and Chemoattraction Are Required for Homing of Insulin-specific CD8(+) T Cells.

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J Exp Med 2003 Mar 3; 197(5):643-656.


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.