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PLoS Pathog. 2014 Jun 26;10(6):e1004210. doi: 10.1371/journal.ppat.1004210. eCollection 2014 Jun.

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

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Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR), Singapore.
Program Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
NIHR Biomedical Research Centre, John Radcliffe Hospital & Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
Institute of Cell and Molecular Science, Barts and the London School of Medicine & Dentistry, London, United Kingdom.
Asian American Liver Centre, Singapore.
Experimental Immunology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR), Singapore; Program Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore; School of Immunity and Infection, College of Medical and Dental Science, University of Birmingham, Edgbaston Birmingham, United Kingdom.


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-γ. 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-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ 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-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.

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