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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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 3

Activation of TLR3 and regulation of Icam-1, Vcam-1, and Cxcl9.

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Activation of TLR3 and regulation of Icam-1, Vcam-1, ...
(A–E) Mice were treated with poly(I:C). After 24 hours, RT-PCR analysis was performed in livers from C57BL/6 mice (n = 3) for Icam-1, Vcam-1, and Cxcl9 (A); Cxcl9 in livers from BALB/c and Tlr3–/– mice and Tlr3–/–→BALB/c and BALB/c→Tlr3–/– bone marrow chimeras (B); Cxcl9 (C) or Vcam-1 (D) in livers from Ifnar–/–, Ifngr–/–, and Tnfr1–/– mice plus corresponding wild-type controls (n = 3). (E) Eight hours after poly(I:C) treatment, blood and spleen cells of C57BL/6 mice were analyzed for surface expression of CXCR3 by flow cytometry. Histogram plots show CD8+ T cells gated for low CD44 expression (naive CD8+ T cells, gray shaded area) or high CD44 expression (memory CD8+ T cells, black line; 15%–20% of all CD8+ T cells). (F–J) 107 splenocytes from LCMV-gp33/H-2Db–specific TCR-Tg 318 mice were injected i.v. into C57BL/6 mice (F–I) or Alb-1 mice (J) on day –1. Recipients were then immunized with gp33 (1 mg in PBS) together with CpG on days 0 and 4. One group of mice was additionally treated with poly(I:C) on day 7. On day 8, livers were analyzed for Cxcl9 by RT-PCR (F) or VCAM-1 by histology (magnification, ×200) (G). Ten hours after poly(I:C) treatment, mice were analyzed for expression of CXCR3 on tet-gp33+ CD8+ splenocytes (H) and for absolute numbers of tet-gp33+ CD8+ T cells in the blood (I). (J) Livers of immunized Alb-1 mice were analyzed for the presence of autoreactive T cells using anti-CD90.1/Thy1.1 antibody (magnification, ×50, ×200). *P < 0.05.