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.
Lang
Karl S
KS
Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland. karl.lang@usz.ch
Georgiev
Panco
P
Recher
Mike
M
Navarini
Alexander A
AA
Bergthaler
Andreas
A
Heikenwalder
Mathias
M
Harris
Nicola L
NL
Junt
Tobias
T
Odermatt
Bernhard
B
Clavien
Pierre-Alain
PA
Pircher
Hanspeter
H
Akira
Shizuo
S
Hengartner
Hans
H
Zinkernagel
Rolf M
RM
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D007739:L Cells; D008099:Liver / Q000276:immunology*; D008107:Liver Diseases / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016898:Interferon-alpha; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D051196:Toll-Like Receptor 3; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1