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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

317 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)138-145
Number of pages8
JournalNature Medicine
Volume11
Issue number2
DOIs
Publication statusPublished - 1 Feb 2005
Externally publishedYes

Bibliographical note

A corrigendum exists for this article, and can be found in Nature Medicine (2005) Vol 11, 1256. at https://doi.org/10.1038/nm1105-1256

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    Lang, K. S., Recher, M., Junt, T., Navarini, A. A., Harris, N. L., Freigang, S., ... Zinkernagel, R. M. (2005). Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nature Medicine, 11(2), 138-145. https://doi.org/10.1038/nm1176