Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease
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.
Keywords: Animals ; Autoimmune Diseases/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Diabetes Mellitus, Type 1/*immunology/virology ; Genes, MHC Class I ; Humans ; Interferon-alpha/immunology ; Islets of Langerhans/cytology/metabolism/physiology ; Lymphocyte Activation ; Lymphocytic choriomeningitis virus/genetics/metabolism ; Membrane Glycoproteins/genetics/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Rats ; Receptors, Cell Surface/genetics/*immunology ; Toll-Like Receptors ; Transgenes ; Viral Proteins/genetics/metabolism
Lang, Karl S Recher, Mike Junt, Tobias Navarini, Alexander A Harris, Nicola L Freigang, Stefan Odermatt, Bernhard Conrad, Curdin Ittner, Lars M Bauer, Stefan Luther, Sanjiv A Uematsu, Satoshi Akira, Shizuo Hengartner, Hans Zinkernagel, Rolf M Research Support, Non-U.S. Gov't United States Nature medicine Nat Med. 2005 Feb;11(2):138-45. Epub 2005 Jan 16.
Record created on 2010-01-06, modified on 2016-08-08