Signalling through C-type lectin receptors: shaping immune responses.
Signalling through C-type lectin receptors: shaping immune responses.
复制标题
DOI：
10.1038/nri2569
复制
发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Gringhuis SI
中科院分区：
文献类型：
--
作者：
Geijtenbeek TB;Gringhuis SI
树突状细胞表达的模式识别受体（PRR）之间的串扰通过诱导针对入侵病原体定制的特异性细胞因子表达谱来协调T辅助（TH）细胞分化。C型凝集素受体（CLRs）在协调诱导调节适应性免疫应答的信号传导途径中具有重要作用。CLR可以通过自身诱导信号传导、通过与其他PRR的串扰或通过诱导碳水化合物特异性信号传导途径来控制各种水平的适应性免疫。DC特异性ICAM 3抓取非整联蛋白（DC-SIGN）与携带甘露糖的病原体（包括结核分枝杆菌、HIV-1、麻疹病毒和白色念珠菌）相互作用以激活丝氨酸/苏氨酸蛋白激酶RAF 1。RAF 1信号传导导致Toll样受体（TLR）激活的核因子-κB（NF-κB）亚基p65的乙酰化并影响细胞因子表达，例如诱导白细胞介素-10（IL-10）的上调。DC相关的C型凝集素1（dectin 1）可被广泛的真菌病原体，如C。白念珠菌、烟曲霉和卡氏肺孢子虫通过两个独立的信号通路的相互作用（一个通过脾酪氨酸激酶（SYK），一个通过RAF 1）产生保护性抗真菌免疫，这两个信号通路对于TH 1和TH 17细胞极化细胞因子的表达是必需的。SYK和RAF 1通路之间的相互作用对于微调NF-κB活性具有协同和拮抗作用：尽管p65的Ser 276磷酸化通过乙酰化导致p65自身的转录活性增强，但它也通过将NF-κB亚基RELB隔离在转录失活的p65-RELB二聚体中来抑制其转录活性。CLR介导的信号转导的多样性为研究阐明和操纵这个激动人心的受体家族的信号转导特性提供了一些主要挑战。然而，最近的进展强烈支持使用树突状细胞来诱导或重定向适应性免疫应答以及改善抗原递送的靶向疫苗接种策略的使用。在这里，Teunis Geijtenbeek和Sonja Gringhuis讨论了C型凝集素受体诱导的信号通路在决定T辅助细胞谱系定型中的作用，并描述了如何利用这些通路开发新的疫苗接种策略。由树突状细胞表达的C型凝集素受体（CLRs）对于定制针对病原体的免疫应答至关重要。病原体结合后，CLR触发不同的信号传导途径，诱导决定T细胞极化命运的特异性细胞因子的表达。一些CLR可以诱导直接激活核因子-κB的信号传导途径，而其他CLR影响Toll样受体的信号传导。剖析这些信号通路及其对宿主免疫细胞的影响对于理解诱导适应性免疫应答的分子机制至关重要。在这篇综述中，我们描述了免疫信号在调节适应性免疫和免疫发病机制中的作用，并讨论了如何利用这些知识来开发创新的疫苗接种方法。
Crosstalk between pattern recognition receptors (PRRs) expressed by dendritic cells orchestrates T helper (TH) cell differentiation through the induction of specific cytokine expression profiles, tailored to invading pathogens. C-type lectin receptors (CLRs) have an important role in orchestrating the induction of signalling pathways that regulate adaptive immune responses. CLRs can control adaptive immunity at various levels by inducing signalling on their own, through crosstalk with other PRRs or by inducing carbohydrate-specific signalling pathways. DC-specific ICAM3-grabbing non-integrin (DC-SIGN) interacts with mannose-carrying pathogens including Mycobacterium tuberculosis, HIV-1, measles virus and Candida albicans to activate the serine/threonine protein kinase RAF1. RAF1 signalling leads to the acetylation of Toll-like receptor (TLR)-activated nuclear factor-κB (NF-κB) subunit p65 and affects cytokine expression, such as inducing the upregulation of interleukin-10 (IL-10). DC-associated C-type lectin 1 (dectin 1) triggering by a broad range of fungal pathogens, such as C. albicans, Aspergillus fumigatus and Pneumocystis carinii, results in protective antifungal immunity through the crosstalk of two independent signalling pathways — one through spleen tyrosine kinase (SYK) and one through RAF1 — that are essential for the expression of TH1 and TH17 cell polarizing cytokines. Crosstalk between the SYK and RAF1 pathways is both synergistic and antagonizing to fine-tune NF-κB activity: although Ser276 phosphorylation of p65 leads to enhanced transcriptional activity of p65 itself through acetylation, it also inhibits the transcriptional activity of the NF-κB subunit RELB by sequestering it in p65–RELB dimers, which are transcriptionally inactive. The diversity in CLR-mediated signalling provides some major challenges for the researches to elucidate and manipulate the signalling properties of this exciting family of receptors. However, the recent advances strongly support the use of CLR targeting vaccination strategies using dendritic cells to induce or redirect adaptive immune responses as well as improve antigen delivery. Here, Teunis Geijtenbeek and Sonja Gringhuis discuss the role of the signalling pathways induced by C-type lectin receptors in determining T helper cell lineage commitment and describe how these pathways can be exploited for the development of new vaccination strategies. C-type lectin receptors (CLRs) expressed by dendritic cells are crucial for tailoring immune responses to pathogens. Following pathogen binding, CLRs trigger distinct signalling pathways that induce the expression of specific cytokines which determine T cell polarization fates. Some CLRs can induce signalling pathways that directly activate nuclear factor-κB, whereas other CLRs affect signalling by Toll-like receptors. Dissecting these signalling pathways and their effects on host immune cells is essential to understand the molecular mechanisms involved in the induction of adaptive immune responses. In this Review we describe the role of CLR signalling in regulating adaptive immunity and immunopathogenesis and discuss how this knowledge can be harnessed for the development of innovative vaccination approaches.
登录
查看更多内容
影响因子：
32.4
作者：
Dejardin, E;Droin, NM;Green, DR
通讯作者：
Green, DR
影响因子：
6.7
作者：
de Witte, Lot;de Vries, Rory D.;van der Vlist, Michiel;Yuksel, Selma;Litjens, Manja;de Swart, Rik L.;Geijtenbeek, Teunis B. H.
通讯作者：
Geijtenbeek, Teunis B. H.
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：
15.9
作者：
Dillon, S;Agrawal, S;Pulendran, B
通讯作者：
Pulendran, B
影响因子：
30.5
作者：
Claudio, E;Brown, K;Siebenlist, U
通讯作者：
Siebenlist, U