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Article
Nature Medicine 11, 138 - 145 (2005)
Published online: 16 January 2005 | doi:10.1038/nm1176
There is a Corrigendum (November 2005) associated with this Article.
Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease
Karl S Lang1,7, Mike Recher1,7, Tobias Junt1, Alexander A Navarini1, Nicola L Harris1, Stefan Freigang1, Bernhard Odermatt1, Curdin Conrad2, Lars M Ittner3, Stefan Bauer4, Sanjiv A Luther5, Satoshi Uematsu6, Shizuo Akira6, Hans Hengartner1 & Rolf M Zinkernagel1
Abstract
Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8+ T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor–triggered interferon-
production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.
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