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Islet-Specific Expression of CXCL10 Causes Spontaneous Islet Infiltration and Accelerates Diabetes Development¹

Antje Rhode^*, Mary E. Pauza, Ana Maria Barral^*, Evelyn Rodrigo^*, Michael B. A. Oldstone, Matthias G. von Herrath^* and Urs Christen^2,*,

^* Immune Regulation Laboratory, Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702; and Division of Virology, Department of Neuropharmacology and Department of Infectology, The Scripps Research Institute, La Jolla, CA 92037; and Pharmacenter, Johann Wolfgang Goethe University, Frankfurt-am-Main, Germany

During inflammation, chemokines are conductors of lymphocyte trafficking. The chemokine CXCL10 is expressed early after virus infection. In a virus-induced mouse model for type 1 diabetes, CXCL10 blockade abrogated disease by interfering with trafficking of autoaggressive lymphocytes to the pancreas. We have generated transgenic rat insulin promotor (RIP)-CXCL10 mice expressing CXCL10 in the cells of the islets of Langerhans to evaluate how bystander inflammation influences autoimmunity. RIP-CXCL10 mice have islet infiltrations by mononuclear cells and limited impairment of cell function, but not spontaneous diabetes. RIP-CXCL10 mice crossed to RIP-nucleoprotein (NP) mice expressing the NP of the lymphocytic choriomeningitis virus in the cells had massively accelerated type 1 diabetes after lymphocytic choriomeningitis virus infection. Mechanistically, we found a drastic increase in NP-specific, autoaggressive CD8 T cells in the pancreas after infection. In situ staining with H-2D^b(NP₃₉₆) tetramers revealed islet infiltration by NP-specific CD8 T cells in RIP-NP-CXCL10 mice early after infection. Our results indicate that CXCL10 expression accelerates the autoimmune process by enhancing the migration of Ag-specific lymphocytes to their target site.

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