Department of Pathology, Emory University, Atlanta, GA 30322, USA.
Eur J Immunol. 2010 Dec;40(12):3528-34. doi: 10.1002/eji.201040421.
The fact that some TLR-based vaccine adjuvants maintain function in TLR-deficient hosts highlights that their mechanism of function remains incompletely understood. Thus, we examined the ability of flagellin to induce cytokines and elicit/promote murine antibody responses upon deletion of the flagellin receptors TLR5 and/or NLRC4 (also referred to as IPAF) using a prime/boost regimen. In TLR5-KO mice, flagellin failed to induce NF-κB-regulated cytokines such as keratinocyte-derived chemokine (CXCL1) but induced WT levels of the inflammasome cytokine IL-18 (IL-1F4). Conversely, in NLRC4-KO mice, flagellin induced keratinocyte-derived chemokine, but not IL-18, whereas TLR5/NLRC4-DKO lacked induction of all cytokines measured. Flagellin/ovalbumin treatment resulted in high-antibody titers to both flagellin and ovalbumin in WT, TLR5-KO and DKO mice but did not elicit antibodies to either in TLR5/NLRC4-DKO mice. Thus, flagellin's ability to elicit/promote humoral immunity requires a germ-line-encoded receptor capable of recognizing this molecule. Such promotion of adaptive immunity can be effectively driven by either TLR5-mediated activation of NF-κB or NLRC4-mediated activation of the inflammasome.
一些 TLR 为基础的疫苗佐剂在 TLR 缺陷型宿主中仍保持功能，这一事实突出表明，其作用机制仍不完全清楚。因此，我们研究了鞭毛蛋白在缺失鞭毛蛋白受体 TLR5 和/或 NLRC4（也称为 IPAF）的情况下，通过初次免疫-加强免疫方案诱导细胞因子产生和引发/促进小鼠抗体应答的能力。在 TLR5-KO 小鼠中，鞭毛蛋白未能诱导 NF-κB 调节的细胞因子，如角质细胞衍生的趋化因子（CXCL1），但诱导了 WT 水平的炎性体细胞因子 IL-18（IL-1F4）。相反，在 NLRC4-KO 小鼠中，鞭毛蛋白诱导角质细胞衍生的趋化因子，但不诱导 IL-18，而 TLR5/NLRC4-DKO 则缺乏所有测量的细胞因子的诱导。鞭毛蛋白/卵清蛋白处理导致 WT、TLR5-KO 和 DKO 小鼠对鞭毛蛋白和卵清蛋白均产生高抗体滴度，但在 TLR5/NLRC4-DKO 小鼠中既不诱导针对任何一种的抗体。因此，鞭毛蛋白诱导/促进体液免疫的能力需要一种能够识别该分子的种系编码受体。这种适应性免疫的促进可以通过 TLR5 介导的 NF-κB 激活或 NLRC4 介导的炎性体激活来有效地驱动。
