Selective C-Rel activation via Malt1 controls anti-fungal T(H)-17 immunity by dectin-1 and dectin-2.
Selective C-Rel activation via Malt1 controls anti-fungal T(H)-17 immunity by dectin-1 and dectin-2.
复制标题
DOI：
10.1371/journal.ppat.1001259
复制
发表时间：
2011-01-20
期刊：
影响因子：
6.7
通讯作者：
Geijtenbeek TB
中科院分区：
文献类型：
--
作者：
Gringhuis SI;Wevers BA;Kaptein TM;van Capel TM;Theelen B;Boekhout T;de Jong EC;Geijtenbeek TB
树突状细胞上的C型凝集素dectin-1和dectin-2通过诱导TH-1和TH-17细胞应答而引起针对真菌感染的保护性免疫。人类树突状细胞上dectin-1的真菌识别与CARD 9-Bcl 10-Malt 1模块结合以激活NF-κB。在这里，我们证明了Malt 1募集是通过选择性激活NF-κB亚基c-Rel，诱导TH-17极化细胞因子IL-1β和IL-23 p19表达的TH-17免疫的关键。Malt 1抑制消除c-Rel激活和TH-17对念珠菌属物种的免疫。我们发现，Malt 1介导的c-Rel激活对dectin-2诱导TH-17极化细胞因子同样重要。而dectin-1激活所有NF-κB亚基，dectin-2选择性激活c-Rel，表明dectin-2在人树突状细胞的抗真菌免疫中具有特异性TH-17增强功能。因此，dectin-1和dectin-2控制适应性TH-17免疫真菌通过麦芽1依赖性激活c-Rel。真菌感染是一种主要的健康威胁，其发病率在全球范围内不断增长。需要有效的抗真菌疫苗。适应性免疫反应，特别是T辅助细胞17型（TH-17）反应在防御真菌感染中至关重要。人树突状细胞（DC）在与真菌相互作用后诱导TH-17应答。DC表达C型凝集素dectin-1和dectin-2，它们与真菌细胞壁中存在的碳水化合物结构相互作用。目前还不清楚这些C型凝集素的信号传导如何导致特异性TH-17应答。在这里，我们证明了存在于CARD 9-Bcl 10-Malt 1复合物中的信号分子Malt 1通过选择性激活NF-κB转录因子c-Rel来负责TH-17诱导，该转录因子c-Rel驱动TH-17极化细胞因子的转录。抑制麦芽糖1或c-Rel防止TH-17诱导响应真菌。此外，我们表明，C型凝集素dectin-2选择性地激活c-Rel，标志着一个专门的TH-17增强功能的C型凝集素。因此，靶向dectin-2或激活Malt 1的新型疫苗接种策略可以诱导主要的TH-17应答。由于异常的TH-17应答是特应性皮炎和各种自身免疫性疾病的病理基础，因此Malt 1是减弱异常适应性免疫应答的合理治疗靶点。
C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel. Fungal infections are a major health threat and the incidence is growing worldwide. There is a need for efficient antifungal vaccines. Adaptive immune responses and in particular T helper cell type 17 (TH-17) responses are crucial in the defence against fungal infections. Human dendritic cells (DCs) induce TH-17 responses after interaction with fungi. DCs express C-type lectins dectin-1 and dectin-2 that interact with the carbohydrate structures present in the cell-wall of fungi. It is unclear how signaling by these C-type lectins leads to specific TH-17 responses. Here we demonstrate that the signaling molecule Malt1 present in the CARD9-Bcl10-Malt1 complex is responsible for TH-17 induction by selectively activating the NF-κB transcription factor c-Rel, which drives transcription of the TH-17-polarizing cytokines. Inhibition of either Malt1 or c-Rel prevents TH-17 induction in response to fungi. Furthermore, we show that the C-type lectin dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for this C-type lectin. Thus, novel vaccination strategies that target dectin-2 or activate Malt1 can induce predominant TH-17 responses. Since aberrant TH-17 responses underlie the pathology of atopic dermatitis and various autoimmune diseases, Malt1 is a rational therapeutic target to attenuate anomalous adaptive immune responses.
登录
查看更多内容
DOI：
10.1038/nri2569
发表时间：
2009-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Geijtenbeek TB;Gringhuis SI
通讯作者：
Gringhuis SI
影响因子：
3.6
作者：
de Jong MA;Vriend LE;Theelen B;Taylor ME;Fluitsma D;Boekhout T;Geijtenbeek TB
通讯作者：
Geijtenbeek TB
影响因子：
30.5
作者：
Coornaert, Beatrice;Baens, Mathijs;Beyaert, Rudi
通讯作者：
Beyaert, Rudi
影响因子：
30.5
作者：
Ferch, Uta;zum Bueschenfelde, Christian Meyer;Ruland, Juergen
通讯作者：
Ruland, Juergen
影响因子：
9.4
作者：
Borman, Andrew M.;Petch, Rebecca;Johnson, Elizabeth M.
通讯作者：
Johnson, Elizabeth M.