The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors
The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors
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DOI：
10.1073/pnas.250476497
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发表时间：
2000-12-05
影响因子：
11.1
通讯作者：
Aderem, A
中科院分区：
文献类型：
--
作者：
Ozinsky, A;Underhill, DM;Aderem, A
Toll样受体（TLR）已被证明参与先天免疫系统对病原体的识别，但尚不清楚受体的有限家族如何具有识别已知存在的广谱TLR刺激的能力。我们在这里报告，TLR家族的两个成员，TLR 2和TLR 6，一起协调巨噬细胞激活革兰氏阳性菌和酵母细胞壁颗粒，酵母聚糖。TLR 6和TLR 2都被募集到巨噬细胞吞噬体，在那里它们识别肽聚糖，一种革兰氏阳性病原体组分。相比之下，TLR 2识别另一种组分，细菌脂肽，而不识别TLRC。TLR合作的要求得到了以下发现的支持：TLR 2需要一个伴侣来激活巨噬细胞中肿瘤坏死因子-α的产生。TLR 2胞质结构域的二聚化不诱导巨噬细胞中肿瘤坏死因子-α的产生，而TLR 4胞质结构域的类似二聚化诱导肿瘤坏死因子-α的产生。我们发现TLR 2的胞质结构域可以与TLRC或TLR 1形成功能性疼痛。并且这种相互作用导致细胞因子诱导。因此，TLR的胞质尾区与某些TLR在功能上不等同，需要组装成异聚复合物，而其他TLR作为同聚复合物是有活性的。最后，我们表明，TLRC，TLR 2和TLR 1被招募到含有IgG包被的红细胞，不显示微生物成分的巨噬细胞吞噬体。这些数据表明，TLR样本的吞噬体的内容物的性质无关的内容物，并可以建立一个组合库，以区分在自然界中发现的大量病原体相关的分子模式。
Toll-like receptors (TLRs) have been shown to participate in the recognition of pathogens by the innate immune system, but it is not dear how a restricted family of receptors has the capacity to recognize the wide spectrum of TLR stimuli known to exist. We report here that two members of the TLR family, TLR2 and TLR6, together coordinate macrophage activation by Gram-positive bacteria and the yeast cell-wall particle, zymosan. TLR6 and TLR2 both are recruited to the macrophage phagosome, where they recognize peptidoglycan, a Gram-positive pathogen component By contrast, TLR2 recognizes another component, bacterial lipopeptide, without TLRC. The requirement for TLR cooperation is supported by the finding that TLR2 needs a partner to activate tumor necrosis factor-alpha production in macrophages. Dimerization of the cytoplasmic domain of TLR2 does not induce tumor necrosis factor-alpha production in macrophages, whereas similar dimerization of the TLR4 cytoplasmic domain does. We show that the cytoplasmic domain of TLR2 can form functional pain with TLRC or TLR1. and this interaction leads to cytokine induction. Thus, the cytoplasmic tails of TLRs are not functionally equivalent with certain TLRs requiring assembly into heteromeric complexes whereas others are active as homomeric complexes. Finally, we show that TLRC, TLR2, and TLR1 are recruited to macrophage phagosomes that contain IgG-coated erythrocytes that do not display microbial components. The data suggest that TLRs sample the contents of the phagosome independent of the nature of the contents, and can establish a combinatorial repertoire to discriminate among the large number of pathogen-associated molecular patterns found in nature.