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Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

2005; Nature Portfolio; Volume: 11; Issue: 2 Linguagem: Inglês

10.1038/nm1176

1546-170X

Karl S. Lang, Mike Recher, Tobias Junt, Alexander A. Navarini, Nicola L. Harris, Stefan Freigang, Bernhard Odermatt, Curdin Conrad, Lars M. Ittner, Stefan Bauer, Sanjiv A. Luther, Satoshi Uematsu, Shizuo Akira, Hans Hengartner, Rolf M. Zinkernagel,

Immune Cell Function and Interaction

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-α production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.