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Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver

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...

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Autores principales: Jo, Juandy, Tan, Anthony T., Ussher, James E., Sandalova, Elena, Tang, Xin-Zi, Tan-Garcia, Alfonso, To, Natalie, Hong, Michelle, Chia, Adeline, Gill, Upkar S., Kennedy, Patrick T., Tan, Kai Chah, Lee, Kang Hoe, De Libero, Gennaro, Gehring, Adam J., Willberg, Christian B., Klenerman, Paul, Bertoletti, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072808/
https://www.ncbi.nlm.nih.gov/pubmed/24967632
http://dx.doi.org/10.1371/journal.ppat.1004210
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author Jo, Juandy
Tan, Anthony T.
Ussher, James E.
Sandalova, Elena
Tang, Xin-Zi
Tan-Garcia, Alfonso
To, Natalie
Hong, Michelle
Chia, Adeline
Gill, Upkar S.
Kennedy, Patrick T.
Tan, Kai Chah
Lee, Kang Hoe
De Libero, Gennaro
Gehring, Adam J.
Willberg, Christian B.
Klenerman, Paul
Bertoletti, Antonio
author_facet Jo, Juandy
Tan, Anthony T.
Ussher, James E.
Sandalova, Elena
Tang, Xin-Zi
Tan-Garcia, Alfonso
To, Natalie
Hong, Michelle
Chia, Adeline
Gill, Upkar S.
Kennedy, Patrick T.
Tan, Kai Chah
Lee, Kang Hoe
De Libero, Gennaro
Gehring, Adam J.
Willberg, Christian B.
Klenerman, Paul
Bertoletti, Antonio
author_sort Jo, Juandy
collection PubMed
description 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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spelling pubmed-40728082014-07-02 Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver Jo, Juandy Tan, Anthony T. Ussher, James E. Sandalova, Elena Tang, Xin-Zi Tan-Garcia, Alfonso To, Natalie Hong, Michelle Chia, Adeline Gill, Upkar S. Kennedy, Patrick T. Tan, Kai Chah Lee, Kang Hoe De Libero, Gennaro Gehring, Adam J. Willberg, Christian B. Klenerman, Paul Bertoletti, Antonio PLoS Pathog Research Article 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. Public Library of Science 2014-06-26 /pmc/articles/PMC4072808/ /pubmed/24967632 http://dx.doi.org/10.1371/journal.ppat.1004210 Text en © 2014 Jo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jo, Juandy
Tan, Anthony T.
Ussher, James E.
Sandalova, Elena
Tang, Xin-Zi
Tan-Garcia, Alfonso
To, Natalie
Hong, Michelle
Chia, Adeline
Gill, Upkar S.
Kennedy, Patrick T.
Tan, Kai Chah
Lee, Kang Hoe
De Libero, Gennaro
Gehring, Adam J.
Willberg, Christian B.
Klenerman, Paul
Bertoletti, Antonio
Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver
title Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver
title_full Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver
title_fullStr Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver
title_full_unstemmed Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver
title_short Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver
title_sort toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072808/
https://www.ncbi.nlm.nih.gov/pubmed/24967632
http://dx.doi.org/10.1371/journal.ppat.1004210
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