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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

1  Institute of Experimental Immunology, University Hospital of Zurich, Schmelzbergstrasse 12, Zurich, Switzerland.

2  Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, Zurich, Switzerland.

3  Research Laboratory for Calcium Metabolism, Clinic Balgrist, University of Zurich, Forchstr. 340, Zurich, Switzerland.

4  Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, TU Munich, Trogerstr. 9, Munich, Germany.

5  Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges, Switzerland.

6  Department of Host Defense, Osaka University, 3-1 Yamada-oka, Suita Osaka, Japan.

7  These authors contributed equally to this work.

Correspondence should be addressed to Karl S Lang karl.lang@usz.ch
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-alpha 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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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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