title: MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant.
abstract: Glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) is a synthetic adjuvant TLR4 agonist that promotes potent poly-functional T(H)1 responses. Different TLR4 agonists may preferentially signal via MyD88 or TIR-domain-containing adapter inducing IFN-beta (TRIF) to exert adjuvant effects; however, the contribution of MyD88 and TRIF signaling to the induction of polyclonal T(H)1 responses by TLR4 agonist adjuvants has not been studied in vivo. To determine whether GLA-SE preferentially signals through MyD88 or TRIF, we evaluated the immune response against a candidate tuberculosis (TB) vaccine Ag following immunization of mice lacking either signaling adapter compared with that of wild-type mice. We find that both MyD88 and TRIF are necessary for GLA-SE to induce a poly-functional T(H)1 immune response characterized by CD4(+) T cells producing IFN-γ, TNF, and IL-2, as well as IgG2c class switching, when paired with the TB vaccine Ag ID93. Accordingly, the protective efficacy of ID93/GLA-SE immunization against aerosolized Mycobacterium tuberculosis was lost when either signaling molecule was ablated. We demonstrate that MyD88 and TRIF must be expressed in the same cell for the in vivo T(H)1-skewing adjuvant activity, indicating that these two signaling pathways cooperate on an intracellular level. Thus engagement of both the MyD88 and TRIF signaling pathways are essential for the effective adjuvant activity of this TLR4 agonist.
authors.affiliation: Infectious Disease Research Institute, Seattle, WA, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Duthie
authors.forename: Hillarie Plessner
authors.initials: HP
authors.lastname: Windish
authors.forename: Elyse A
authors.initials: EA
authors.lastname: Lucas
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Guderian
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hudson
authors.forename: Narek
authors.initials: N
authors.lastname: Shaverdian
authors.forename: Joanne
authors.initials: J
authors.lastname: O'Donnell
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Desbien
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D032581:Tuberculosis Vaccines / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D007371:Interferon-gamma; D007376:Interleukin-2; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG; D051197:Toll-Like Receptor 4; D032581:Tuberculosis Vaccines; D014409:Tumor Necrosis Factor-alpha; C406563:IgG2c receptor; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse
keywords: Adjuvant; CD4+ T cells; GLA; TLR4; Vaccine