Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling
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
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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Research Article Autoimmunity

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 4

Homing is crucial for LCMV-induced autoimmune hepatitis.

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Homing is crucial for LCMV-induced autoimmune hepatitis. (A–C) 107 splen...
(A–C) 107 splenocytes from LCMV-gp33/H-2Db–specific TCR-Tg 318 mice were transferred i.v. into Alb-1+ Ifnar–/– mice (C57BL/6 background) and littermate controls (Alb-1+ Ifnar+/– or Alb-1+ Ifnar+/+) on day –1. Recipients were immunized with 200 pfu LCMV on day 0. (A) On day 7, Alb-1+ Ifnar–/– mice died, and livers were analyzed for CD8+ T cell infiltration and LCMV nucleoprotein (LCMV-NP) by immunohistology (magnification, ×100). (B) CD8+ T cells were analyzed by tetramer staining and in an in vitro CTL assay. (C) Serum was analyzed for bilirubin concentrations, alkaline phosphatase activity (a marker for bile cholestasis), and ALT activity (n = 3 per group). (D) Ifnar–/–mice (Sv129 background without transfer of 318 T cells) and corresponding control mice were infected with 200 pfu LCMV-WE. After 7 days, livers were analyzed for expression of CXCL9. *P > 0.05. (E–H) 107 splenocytes from LCMV-gp33/H-2Db–specific TCR-Tg 318 mice were transferred i.v. into naive Alb-1 mice or C57BL/6 mice on day –1. Recipients were then infected with 200 PFU LCMV-WE on day 0. One group was further treated with 0.5 μg of PTX on days 0 and 3. (E) On day 6, liver sections were analyzed for CD8+ T cell infiltration or for viral antigen (LCMV-NP) by histology (magnification, ×100; n = 2 per group). Serum was analyzed for bilirubin concentration and ALT activity (n = 4 per group) (F), and CD8+ T cell effector function was assessed by an in vitro CTL assay (G). (H) Autoreactive CD8+ T cells and their IL-7Rα expression were analyzed in the blood (n = 4 per group).