Toll-like receptor 4 is required for optimal development of Th2 immune responses: Role of dendritic cells
Toll-like receptor 4 is required for optimal development of Th2 immune responses: Role of dendritic cells
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DOI：
10.4049/jimmunol.168.9.4524
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发表时间：
2002-05-01
影响因子：
4.4
通讯作者：
Lewis, DB
中科院分区：
文献类型：
--
作者：
Dabbagh, K;Dahl, ME;Lewis, DB
LPS通过激活Toll样受体4（TLR 4）有效诱导树突状细胞成熟和促炎细胞因子（例如IL-12）的产生。由于IL-12对于Th 1应答的产生和维持是重要的，并且还可以抑制从初始CD 4 T细胞前体产生Th 2细胞，因此已经推断TLR 4信号传导将通过诱导IL-12分泌而具有类似的作用。令人惊讶的是，我们发现，TLR 4缺陷的小鼠进行致敏和肺部挑战与蛋白质过敏原减少气道炎症与嗜酸性粒细胞，过敏原特异性IgE水平，和Th 2细胞因子的生产，与野生型小鼠相比。这些降低的反应至少部分归因于树突状细胞功能的降低：来自TLR 4缺陷小鼠的树突状细胞表达较低水平的CD 86，这是一种对反应重要的共刺激分子。它们还在体外诱导抗原初始CD 4 T细胞产生较少的Th 2细胞因子，并在体内介导减少的CD 4 T细胞Ag特异性肺部炎症。这些结果表明，TLR 4是所需的最佳的Th 2应答抗原从非病原性来源，并建议TLR 4配体的作用，如LPS来源于大肠杆菌或内源性衍生的配体，在先天性免疫系统的成熟病原体暴露前。
LPS potently induces dendritic cell maturation and the production of proinflammatory cytokines, such as IL-12, by activation of Toll-like receptor 4 (TLR4). Since IL-12 is important for the generation and maintenance of Th1 responses and may also inhibit Th2 cell generation from naive CD4 T cell precursors, it has been inferred that TLR4 signaling would have similar effects via the induction of IL-12 secretion. Surprisingly, we found that TLR4-defective mice subjected to sensitization and pulmonary challenge with a protein allergen had reductions in airway inflammation with eosinophils, allergen-specific IgE levels, and Th2 cytokine production, compared with wild-type mice. These reduced responses were attributable, at least in part, to decreased dendritic cell function: Dendritic cells from TLR4-defective mice expressed lower levels of CD86, a costimulatory molecule important for The responses. They also induced less Th2 cytokine production by antigenically naive CD4 T cells in vitro and mediated diminished CD4 T cell Ag-specific pulmonary inflammation in vivo. These results indicate that TLR4 is required for optimal Th2 responses to Ags from nonpathogenic sources and suggest a role for TLR4 ligands, such as LPS derived from commensal bacteria or endogenously derived ligands, in maturation of the innate immune system before pathogen exposure.