title: Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development.
abstract: 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 beta 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 beta 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 beta 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)(NP(396)) 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.
authors.affiliation: Immune Regulation Laboratory, Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
authors.forename: Antje
authors.initials: A
authors.lastname: Rhode
authors.forename: Mary E
authors.initials: ME
authors.lastname: Pauza
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Barral
authors.forename: Evelyn
authors.initials: E
authors.lastname: Rodrigo
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
authors.forename: Urs
authors.initials: U
authors.lastname: Christen
mesh_terms: D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000821:virology; D007249:Inflammation / Q000276:immunology; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008822:Mice, Transgenic; D037182:T-Cell Antigen Receptor Specificity; D014764:Viral Proteins / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D014764:Viral Proteins