Division of Allergy, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
J Immunol. 2014 Mar 15;192(6):2722-33. doi: 10.4049/jimmunol.1301424. Epub 2014 Feb 14.
Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1- and Th-17-balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell-mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.
水包油型纳米乳（NE）佐剂 W805EC 经鼻腔给药可产生有效的全身和黏膜、Th1 和 Th17 平衡的细胞应答。然而，其作用机制尚未完全阐明，这一点尤其值得关注，因为 NE 不含有先天免疫受体的特定配体。在这些研究中，我们证明 W805EC NE 佐剂通过一种与典型 TLR 激动剂不同的机制激活先天免疫，诱导特定基因转录，并调节 NF-κB 活性，该机制涉及 TLR2 和 TLR4。基于 NE 的疫苗鼻腔免疫表明，TLR2、TLR4 和 MyD88 途径以及 IL-12 和 IL-12Rβ1 表达对于 Ab 应答不是必需的，但对于诱导平衡的 Th1 极化和 Th17 细胞免疫是必需的。NE 佐剂诱导 MHC Ⅱ类、CD80 和 CD86 共刺激分子表达和树突状细胞成熟。此外，用 NE 免疫时，CD86 受体缺陷的佐剂小鼠具有正常的 Ab 应答，但 Th1 细胞应答显著降低，而缺乏 CD80 和 CD86 或缺乏 CD40 的动物则无法产生体液或细胞免疫。总的来说，我们的数据表明，Ag 与 NE 经鼻腔给药可诱导 TLR2 和 TLR4 激活，以及非 MyD88 依赖的 Ab 应答和 MyD88 依赖的 Th1 和 Th17 细胞介导的免疫应答。这些发现表明，NE 佐剂的独特特性可能为理解以前未被认识到的免疫激活机制提供新的机会，这些机制对于产生有效的黏膜和全身免疫应答很重要。
