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TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo

Despite recent advances in developing and licensing adjuvants, there is a great need for more potent formulations to enhance immunogenicity of vaccines. An Eimeria tenella derived antigen (rEA) augments immune responses against several pathogens in animal models and recently was confirmed to be safe...

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Autores principales: Seregin, Sergey S., Aldhamen, Yasser A., Appledorn, Daniel M., Aylsworth, Charles F., Godbehere, Sarah, Liu, Chyong-Jy Joyce, Quiroga, Dionisia, Amalfitano, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132756/
https://www.ncbi.nlm.nih.gov/pubmed/21760953
http://dx.doi.org/10.1371/journal.pone.0022064
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author Seregin, Sergey S.
Aldhamen, Yasser A.
Appledorn, Daniel M.
Aylsworth, Charles F.
Godbehere, Sarah
Liu, Chyong-Jy Joyce
Quiroga, Dionisia
Amalfitano, Andrea
author_facet Seregin, Sergey S.
Aldhamen, Yasser A.
Appledorn, Daniel M.
Aylsworth, Charles F.
Godbehere, Sarah
Liu, Chyong-Jy Joyce
Quiroga, Dionisia
Amalfitano, Andrea
author_sort Seregin, Sergey S.
collection PubMed
description Despite recent advances in developing and licensing adjuvants, there is a great need for more potent formulations to enhance immunogenicity of vaccines. An Eimeria tenella derived antigen (rEA) augments immune responses against several pathogens in animal models and recently was confirmed to be safe for human use. In this study, we have analyzed the molecular mechanisms underlying rEA activity in mice, and confirmed that rEA activates multiple immune cell types, including DCs, macrophages, NK, B, and T cells. The rEA adjuvant also elicits the induction of pleiotropic pro-inflammatory cytokines, responses that completely depend upon the presence of the TLR adaptor protein MyD88. Surprisingly, we also found that the TRIF adaptor protein acts as a potent negative regulator of TLR agonist-triggered immune responses. For example, IL12 production and the induction of co-stimulatory molecule expression by DCs and IFNγ production by NK cells in vivo were significantly increased in rEA-treated TRIF-KO mice. Importantly, however, TRIF suppressive effects were not restricted to rEA-mediated responses, but were apparent in LPS- or ODN2006-activated DCs as well. Taken together, our findings confirm that rEA is a potent adjuvant, triggering robust activation of the innate immune system, in a manner that is augmented by MyD88 and inhibited by TRIF; thereby unveiling the potential complexities of modulating TLR activity to augment vaccine efficacy.
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spelling pubmed-31327562011-07-14 TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo Seregin, Sergey S. Aldhamen, Yasser A. Appledorn, Daniel M. Aylsworth, Charles F. Godbehere, Sarah Liu, Chyong-Jy Joyce Quiroga, Dionisia Amalfitano, Andrea PLoS One Research Article Despite recent advances in developing and licensing adjuvants, there is a great need for more potent formulations to enhance immunogenicity of vaccines. An Eimeria tenella derived antigen (rEA) augments immune responses against several pathogens in animal models and recently was confirmed to be safe for human use. In this study, we have analyzed the molecular mechanisms underlying rEA activity in mice, and confirmed that rEA activates multiple immune cell types, including DCs, macrophages, NK, B, and T cells. The rEA adjuvant also elicits the induction of pleiotropic pro-inflammatory cytokines, responses that completely depend upon the presence of the TLR adaptor protein MyD88. Surprisingly, we also found that the TRIF adaptor protein acts as a potent negative regulator of TLR agonist-triggered immune responses. For example, IL12 production and the induction of co-stimulatory molecule expression by DCs and IFNγ production by NK cells in vivo were significantly increased in rEA-treated TRIF-KO mice. Importantly, however, TRIF suppressive effects were not restricted to rEA-mediated responses, but were apparent in LPS- or ODN2006-activated DCs as well. Taken together, our findings confirm that rEA is a potent adjuvant, triggering robust activation of the innate immune system, in a manner that is augmented by MyD88 and inhibited by TRIF; thereby unveiling the potential complexities of modulating TLR activity to augment vaccine efficacy. Public Library of Science 2011-07-08 /pmc/articles/PMC3132756/ /pubmed/21760953 http://dx.doi.org/10.1371/journal.pone.0022064 Text en Seregin 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
Seregin, Sergey S.
Aldhamen, Yasser A.
Appledorn, Daniel M.
Aylsworth, Charles F.
Godbehere, Sarah
Liu, Chyong-Jy Joyce
Quiroga, Dionisia
Amalfitano, Andrea
TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo
title TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo
title_full TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo
title_fullStr TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo
title_full_unstemmed TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo
title_short TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo
title_sort trif is a critical negative regulator of tlr agonist mediated activation of dendritic cells in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132756/
https://www.ncbi.nlm.nih.gov/pubmed/21760953
http://dx.doi.org/10.1371/journal.pone.0022064
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