Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling
The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.
Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics ; Adoptive Transfer ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Cytotoxicity, Immunologic ; Humans ; Interferon-alpha/biosynthesis ; L Cells (Cell Line) ; Liver/*immunology ; Liver Diseases/*immunology ; Mice ; Mice, Knockout ; Myeloid Differentiation Factor 88 ; Receptors, Tumor Necrosis Factor/deficiency/genetics ; Receptors, Tumor Necrosis Factor, Type I ; Toll-Like Receptor 3/*immunology ; Tumor Necrosis Factor Decoy Receptors ; Tumor Necrosis Factor-alpha/secretion
Lang, Karl S Georgiev, Panco Recher, Mike Navarini, Alexander A Bergthaler, Andreas Heikenwalder, Mathias Harris, Nicola L Junt, Tobias Odermatt, Bernhard Clavien, Pierre-Alain Pircher, Hanspeter Akira, Shizuo Hengartner, Hans Zinkernagel, Rolf M Research Support, Non-U.S. Gov't United States The Journal of clinical investigation J Clin Invest. 2006 Sep;116(9):2456-63.
Record created on 2010-01-06, modified on 2016-08-08