title: TRIF is a critical negative regulator of TLR agonist mediated activation of dendritic cells in vivo.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: Charles F
authors.initials: CF
authors.lastname: Aylsworth
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.forename: Chyong-Jy Joyce
authors.initials: CJ
authors.lastname: Liu
authors.forename: Dionisia
authors.initials: D
authors.lastname: Quiroga
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000469:parasitology; D016786:Eimeria tenella / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology; D010766:Phosphorylation; D000091402:Prohibitins; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000953:Antigens, Protozoan; D018925:Chemokines; D048049:Extracellular Signal-Regulated MAP Kinases; D018836:Inflammation Mediators; D053594:Myeloid Differentiation Factor 88; D000091402:Prohibitins; D051193:Toll-Like Receptors; C000717331:PHB2 protein, human; C476286:Ticam1 protein, mouse