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(American Journal of Pathology. 2007;170:240-250.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060142

Islet ß-Cell-Specific T Cells Can Use Different Homing Mechanisms to Infiltrate and Destroy Pancreatic Islets

Arno Hänninen^*, Rita Nurmela^*, Mikael Maksimow^*, Jarkko Heino^*, Sirpa Jalkanen^* and Christian Kurts

From the MediCity Research Laboratory and Department of Medical Microbiology,^* University of Turku, Turku, Finland; the Turku Graduate School of Biomedical Sciences, Turku, Finland; and the Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany

Organ infiltration by T cells depends on the adhesion molecules expressed in these sites and on homing receptors expressed by the T cells. Here, we have studied which form of priming can enable T cells to home to pancreatic islets. To this end, we have used transgenic mice expressing the model autoantigen ovalbumin in pancreatic islets and transgenic ovalbumin-specific CD4 and CD8 T cells. We demonstrate that these T cells were imprinted with homing receptor patterns characteristic for the site of priming, such as 4ß7 integrin for mucosal antigen delivery or functionally active 4ß1 integrin for islet autoantigens. The adhesion molecules corresponding to these receptors were found to be constitutively expressed in islets, enabling T cells bearing these receptors to infiltrate the islets and to cause diabetes. Disease was prevented only by blockade of the endothelial adhesion molecule, ligand of homing receptors with which the T cells were imprinted. Thus, different priming locations induced different homing mechanisms, allowing T cells to target the islets. This may contribute to the susceptibility of islets to T-cell-mediated attack. Furthermore, it may pertain to the design of adhesion-modulating therapies alone or in combination with external autoantigen administration.

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