Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling
Karl S. Lang, … , Hans Hengartner, Rolf M. Zinkernagel
Karl S. Lang, … , Hans Hengartner, Rolf M. Zinkernagel
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2456-2463. https://doi.org/10.1172/JCI28349.
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Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling

Abstract

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-α and TNF-α 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.

Authors

Karl S. Lang, Panco Georgiev, Mike Recher, Alexander A. Navarini, Andreas Bergthaler, Mathias Heikenwalder, Nicola L. Harris, Tobias Junt, Bernhard Odermatt, Pierre-Alain Clavien, Hanspeter Pircher, Shizuo Akira, Hans Hengartner, Rolf M. Zinkernagel

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Figure 1

TLR3 ligation converts autoreactivity into autoimmune disease.

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TLR3 ligation converts autoreactivity into autoimmune disease. 107 splen...
107 splenocytes from LCMV-gp33/H-2Db–specific TCR-Tg 318 mice were injected i.v. into naive Alb-1 mice or control C57BL/6 mice on day –1. (A) Seven days after transfer, mice were analyzed for gp33-specific T cells and for liver enzymes. Proliferation of transferred cells was analyzed with CFSE (Supplemental Figure 1). (B) After transfer of 318 splenocytes, Alb-1 mice were infected with 200 PFU LCMV-WE on day 0 (filled circles), and numbers of tet-gp33+ CD8+ T cells determined in peripheral blood over time. Serum activities of ALT and bilirubin serum concentrations were also determined (n = 5). *P > 0.05. (C) Mice were immunized with gp33 (1 mg in PBS) and CpG on days 0 and 4 (open squares). A separate group of mice was additionally treated with poly(I:C) on day 7 (arrows) (shaded squares). Numbers of blood tet-gp33+CD8+ T cells, serum ALT activities, and bilirubin serum concentrations were determined (n = 5–7 per group).