Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses
Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses
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DOI：
10.1074/jbc.m502900200
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发表时间：
2006-08-11
影响因子：
4.8
通讯作者：
Schild, Hansjoerg
中科院分区：
文献类型：
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作者：
Warger, Tobias;Hilf, Nobert;Schild, Hansjoerg
toll样受体（TLR）配体激活树突状细胞是启动先天和适应性免疫反应的关键事件。已经确定了几种TLR配体，它们与TLR家族的不同成员相互作用。TLR4配体包括来自不同革兰氏阴性菌和病毒蛋白的脂多糖。最近的报道已经证明了tlr介导的树突状细胞被热休克蛋白（HSPs）激活。然而，对于这种影响在多大程度上是由于热休克蛋白制剂的脂多糖污染引起的，人们提出了疑问。我们使用Gp96或其n端结构域（名义上不含内毒素（< 0.5酶单位/mg））重新检查了这一现象。如前所述，先天免疫细胞在高浓度（50 μ g/ml）下被Gp96激活，但在较低浓度下不被激活。然而，将低量Gp96与TLR2和TLR4配体预先孵育在自身无法激活树突状细胞的浓度下，会导致高水平的促炎细胞因子的产生，激活标记物的上调，以及T细胞活化的扩增。我们的研究结果为热休克蛋白介导的树突状细胞活化机制提供了重要的新见解，并提出了热休克蛋白在细菌产物扩增树突状细胞活化和诱导适应性免疫反应中的新功能。
Activation of dendritic cells by ligands for Toll-like receptors (TLR) is a crucial event in the initiation of innate and adaptive immune responses. Several classes of TLR ligands have been identified that interact with distinct members of the TLR-family. TLR4 ligands include lipopolysaccharide derived from different Gram-negative bacteria and viral proteins. Recent reports have demonstrated the TLR-mediated activation of dendritic cells by heat shock proteins (HSPs). However, doubts were raised as to what extent this effect was due to lipopolysaccharide contaminations of the HSP preparations. We re-examined this phenomenon using Gp96 or its N-terminal domain, nominally endotoxin-free (< 0.5 enzyme units/mg). As described previously, innate immune cells are activated by Gp96 at high concentrations (> 50 mu g/ml) but not at lower concentrations. However, preincubation of low amounts of Gp96 with TLR2 and TLR4 ligands at concentrations unable to activate dendritic cells by themselves results in the production of high levels of proinflammatory cytokines, up-regulation of activation markers, and amplification of T cell activation. Our results provide significant new insights into the mechanism of HSP-mediated dendritic cell activation and present a new function of HSPs in the amplification of dendritic cell activation by bacterial products and induction of adaptive immune responses.