Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity
Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity
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DOI：
10.1038/nature04926
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发表时间：
2006-08-10
期刊：
影响因子：
64.8
通讯作者：
Ruland, Juergen
中科院分区：
文献类型：
--
作者：
Gross, Olaf;Gewies, Andreas;Ruland, Juergen
由于包括艾滋病在内的免疫缺陷的显著增加，真菌感染在世界范围内正在增加；然而，对真菌的免疫反应知之甚少。Dectin- 1是哺乳动物真菌成分酵素的主要模式识别受体。Dectin- 1代表了先天非Toll样受体（TLRs）的原型，其中含有与适应性抗原受体相关的免疫受体酪氨酸激活基序（ITAMs）。在这里，我们确定Card9是Dectin- 1信号的关键换能器。虽然Card9在TLR/ MyD88诱导的应答中是不可缺少的，但它控制着Dectin- 1介导的髓细胞活化、细胞因子的产生和先天抗真菌免疫。Card9与Bcl10偶联，调节酵素诱导的Bcl10 - Malt1介导的NF- kappa B活化。然而，Card9对于使用Carma1作为连接Bcl10 - Malt1的抗原受体信号传导是必不可少的。因此，我们的研究结果定义了一种新的先天免疫途径，并表明先天免疫细胞和适应性免疫细胞中进化上不同的ITAM受体使用不同的接头蛋白选择性地参与保守的Bcl10 - Malt1模块。
Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin- 1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin- 1 represents the prototype of innate non- Toll- like receptors ( TLRs) containing immunoreceptor tyrosine- based activation motifs ( ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin- 1 signalling. Although being dispensable for TLR/ MyD88- induced responses, Card9 controls Dectin- 1- mediated myeloid cell activation, cytokine production and innate anti- fungal immunity. Card9 couples to Bcl10 and regulates Bcl10 - Malt1- mediated NF- kappa B activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10 - Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10 - Malt1 module.