title: The TLR4 Agonist Vaccine Adjuvant, GLA-SE, Requires Canonical and Atypical Mechanisms of Action for TH1 Induction.
abstract: The Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) promotes strong TH1 and balanced IgG1/IgG2 responses to protein vaccine antigens. This enhanced immunity is sufficient to provide protection against many diseases including tuberculosis and leishmaniasis. To better characterize the adjuvant action it is important to understand how the different cytokines and transcription factors contribute to the initiation of immunity. In the present study using T-bet-/- and IL-12-/- mice and a blocking anti-IFNαR1 monoclonal antibody, we define mechanisms of adjuvant activity of GLA-SE. In accordance with previous studies of TLR4 agonist based adjuvants, we found that TH1 induction via GLA-SE was completely dependent upon T-bet, a key transcription factor for IFNγ production and TH1 differentiation. Consistent with this, deficiency of IL-12, a cytokine canonical to TH1 induction, ablated TH1 induction via GLA-SE. Finally we demonstrate that the innate immune response to GLA-SE, including rapid IFNγ production by memory CD8+ T cells and NK cells, was contingent on type I interferon, a cytokine group whose association with TH1 induction is contextual, and that they contributed to the adjuvant activity of GLA-SE.
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Natasha
authors.initials: N
authors.lastname: Dubois Cauwelaert
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Desbien
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hudson
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Pine
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.|Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.|Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.|Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D005960:Glucosides / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D008050:Lipid A / Q000494:pharmacology*; D051379:Mice; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D005960:Glucosides; D008050:Lipid A; C000608161:glucopyranosyl lipid-A