Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver

Jo, Juandy and Tandrapah, Anthony T. and Ussher, James E. and Sandalova, Elena and Tang, Xin-Zi and Tan-Garcia, Alfonso and Touchet, Natalie and Hong, Michelle and Chia, Adeline and Gill, Upkar S. and Kennedy, Patrick T. and Tan, Kai Chah and Lee, Kang Hoe and De Libero, Gennaro and Gehring, Adam J. and Willberg, Christian B. and Klenerman, Paul and Bertoletti, Antonio. (2014) Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLoS Pathogens, 10 (6). e1004210.

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Official URL: https://edoc.unibas.ch/61655/

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The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-gamma. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-gamma, without the concomitant production of TNF-alpha or IL-17A. The intrahepatic IFN-gamma production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-gamma upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Experimental Immunology (De Libero)
UniBasel Contributors:De Libero, Gennaro
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Public Library of Science
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Jul 2020 13:42
Deposited On:21 Jul 2020 11:48

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