MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant

Mark T. Orr, Malcolm S. Duthie, Hillarie Plessner Windish, Elyse A. Lucas, Jeffrey A. Guderian, Thomas E. Hudson, Narek Shaverdian, Joanne O'Donnell, Anthony L. Desbien, Steven G. Reed, Rhea N. Coler

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51 Citations (Scopus)

Abstract

Glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) is a synthetic adjuvant TLR4 agonist that promotes potent poly-functional TH1 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 TH1 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 TH1 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 TH1-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.

Original languageEnglish
Pages (from-to)2398-2408
Number of pages11
JournalEuropean Journal of Immunology
Volume43
Issue number9
DOIs
Publication statusPublished - Sep 2013
Externally publishedYes

Keywords

  • Adjuvant
  • CD4 T cells
  • GLA
  • TLR4
  • Vaccine

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