The Journal of Experimental Medicine
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Published online 24 February 2003 doi:10.1084/jem.20021378
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© Rockefeller University Press, 0022-1007/2003/3/643 $5.00
The Journal of Experimental Medicine, Volume 197, Number 5, 643-656

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

Alexei Y. Savinov1, F. Susan Wong2, Austin C. Stonebraker1 and Alexander V. Chervonsky1

1 The Jackson Laboratory, Bar Harbor, ME 04609
2 The Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom

Address correspondence to Dr. Alexander V. Chervonsky, The Jackson Laboratory, Bar Harbor, ME 04609. Phone: 207-288-6289; Fax: 207-288-6078; E-mail: avc{at}jax.org

Activated insulin-specific CD8+ T cells (IS-CD8+ cells) home to the pancreas, destroy ß 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 ß 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.

Key Words: autoimmunity • diabetes • chemokines • CD8 T cells • homing


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