Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development.
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.
Rhode
Antje
A
Immune Regulation Laboratory, Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Pauza
Mary E
ME
Barral
Ana Maria
AM
Rodrigo
Evelyn
E
Oldstone
Michael B A
MB
von Herrath
Matthias G
MG
Christen
Urs
U
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
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D014764:Viral Proteins