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.
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We thank A. Aguzzi, M. Heikenwälder and C. Sigurdson for ideas, discussions and critical comments. Additionally, we thank K. Tschannen for technical support and A. Nowotny and S. Behnke for histological analysis. This study was supported by the Swiss National Science Foundation and Deutsche Forschungsgemeinschaft (DFG) LA1419/1-1.
The authors declare no competing financial interests.
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Lang, K., Recher, M., Junt, T. et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med 11, 138–145 (2005) doi:10.1038/nm1176
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