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

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  • A Corrigendum to this article was published on 01 November 2005


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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Figure 1: Expansion of CD8+ T cells specific for beta islet cell antigen alone does not necessarily induce diabetes.
Figure 2: Peptide immunization induces highly activated CTLs.
Figure 3: Pancreatic infiltration by activated beta islet-specific CD8+ T cells is not sufficient to induce diabetes.
Figure 4: LCMV infection, but not peptide immunization, results in MHC class I upregulation on beta islet cells.
Figure 5: Toll-like receptor stimulation induces MHC class I upregulation on beta islet cells.
Figure 6: Prevention of LCMV-induced diabetes by lack of MyD88 or IFN type I receptor.


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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.

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Correspondence to Karl S Lang.

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Supplementary information

Supplementary Fig. 1

Kinetics of MHC I up-regulation after Toll-like receptor stimulation (PDF 183 kb)

Supplementary Fig. 2

Source of IFN-α (PDF 275 kb)

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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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