Infectious Disease Research Institute, Seattle, WA, USA.
Eur J Immunol. 2013 Sep;43(9):2398-408. doi: 10.1002/eji.201243124. Epub 2013 Jul 3.
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.
葡聚糖脂质佐剂稳定乳液（GLA-SE）是一种合成的 TLR4 激动剂佐剂，可促进有效的多功能 T(H)1 反应。不同的 TLR4 激动剂可能优先通过 MyD88 或 TIR 结构域包含衔接子诱导 IFN-β（TRIF）信号传导来发挥佐剂作用；然而，TLR4 激动剂佐剂诱导多克隆 T(H)1 反应中 MyD88 和 TRIF 信号传导的贡献尚未在体内进行研究。为了确定 GLA-SE 是否优先通过 MyD88 或 TRIF 信号传导，我们评估了缺乏信号传导衔接子的小鼠与野生型小鼠相比，针对候选结核病（TB）疫苗 Ag 的免疫反应。我们发现，MyD88 和 TRIF 对于 GLA-SE 诱导以 CD4(+)T 细胞产生 IFN-γ、TNF 和 IL-2 以及 IgG2c 类转换为特征的多功能 T(H)1 免疫反应都是必需的，当与 TB 疫苗 Ag ID93 配对时也是如此。因此，当两种信号分子被消融时，ID93/GLA-SE 免疫接种对雾化分枝杆菌的保护效力丧失。我们证明，MyD88 和 TRIF 必须在同一细胞中表达，才能在体内产生 T(H)1 偏向佐剂活性，这表明这两种信号通路在细胞内合作。因此，TLR4 激动剂佐剂的有效佐剂活性需要这两种信号通路的参与。
