Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells.
Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells.
复制标题
DOI：
10.1371/journal.pbio.1001658
复制
发表时间：
2013-09
期刊：
影响因子：
9.8
通讯作者：
Paul S
中科院分区：
文献类型：
--
作者：
Rochereau N;Drocourt D;Perouzel E;Pavot V;Redelinghuys P;Brown GD;Tiraby G;Roblin X;Verrier B;Genin C;Corthésy B;Paul S
这项工作报告了期待已久的Dectin-1和Siglec-5作为M细胞共受体的鉴定，它们介导分泌型伊加分子的反向转胞吞作用以产生肠道免疫应答。肠微折叠（M）细胞具有高的转胞吞能力，并且能够将包括颗粒抗原、可溶性大分子和病原体的广泛范围的材料从肠腔转运至粘膜免疫系统的诱导位点。M细胞也是将分泌型伊加（SIgA）递送至肠相关淋巴组织的主要途径。然而，尽管现在已熟知并描述了M细胞摄取SIgA的后果，但对SIgA选择性结合和摄取的机制仍知之甚少。在这里，我们首先证明了Cα1区和糖基化，更具体地说，唾液酸残基，参与M细胞介导的反向转胞吞。其次，我们发现SIgA通过Dectin-1受体被M细胞摄取，Siglec-5可能参与其中，作为共受体。第三，我们建立了转胞吞的SIgA被粘膜CX 3CR 1+树突状细胞（DC）通过DC-SIGN受体摄取。第四，我们表明，粘膜和全身抗体对艾滋病毒p24-SIgA复合物口服给药的反应是严格依赖于Dectin-1的表达。已经破译了导致基于SIgA的Ag复合物的特异性靶向的机制，为使用这种载体进行针对各种传染病的粘膜疫苗接种铺平了道路。分泌型伊加（SIgA）抗体被分泌到肠腔中，并且被认为是保护肠上皮免受肠道病原体侵害的第一道防线。SIgA巡逻粘液，通常已知通过捕获饮食抗原和微生物以及其他机制来帮助免疫耐受。与其抗原复合的SIgA也可以在称为反向胞吞作用的过程中被肠上皮细胞重新吸收。因此，SIgA可以促进抗原从肠腔到肠相关类淋巴组织（GALT）的摄取和递送，从而影响炎症反应。这种SIgA的反向转胞吞作用由特化的上皮M细胞介导。由于M细胞具有摄取抗原的能力，因此对局部免疫系统很重要，因此它们是针对各种疾病的新型粘膜疫苗特异性递送的关键靶标。M细胞受体，采取了SIgA-抗原复合物，作为粘膜疫苗的车辆，代表了这种疫苗策略的一个重要方面。然而，在M细胞表面上的SIgA受体的鉴定十多年来仍然难以捉摸。在这项研究中，我们现在确定Dectin-1和Siglec-5作为M细胞介导的SIgA复合物反向转胞吞作用的关键受体。我们进一步发现，SIgA的糖基化修饰，特别是唾液酸化是其被M细胞摄取所必需的。我们表明，当口服与SIgA复合时，HIV p24抗原以严格的Dectin-1依赖性方式被吸收，以刺激粘膜和全身抗体应答。这些发现被认为对理解肠道免疫很重要。
This work reports the long-awaited identification of Dectin-1 and Siglec-5 as the M cell co-receptors that mediate the reverse transcytosis of secretory IgA molecules to mount a gut immune response. Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell–mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1+ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases. Secretory IgA (SIgA) antibodies are secreted into the gut lumen and are considered to be a first line of defense in protecting the intestinal epithelium from gut pathogens. SIgA patrol the mucus and are usually known to help immune tolerance via entrapping dietary antigens and microorganisms and other mechanisms. SIgA, in complex with its antigens, can also be taken back up by the intestinal epithelium in a process known as reverse transcytosis. SIgA can thereby promote the uptake and delivery of antigens from the intestinal lumen to the Gut-Associated Lymphoid Tissues (GALT), influencing inflammatory responses. This reverse transcytosis of SIgA is mediated by specialized epithelial M cells. Because M cells possess the ability to take up antigens and are therefore important to the local immune system, they are a key target for the specific delivery of novel mucosal vaccines against various diseases. M cell receptors that take up the SIgA-antigen complexes, which serve as mucosal vaccine vehicles, represent an important aspect of this vaccine strategy. The identification of SIgA receptor(s) on the surface of M cells has, however, remained elusive for more than a decade. In this study, we now identify Dectin-1 and Siglec-5 as the key receptors for M cell–mediated reverse transcytosis of SIgA complexes. We further find that the glycosylation modification, and particularly sialylation, of SIgA is required for its uptake by M cells. We show that, when administered orally in complex with SIgA, the HIV p24 antigen is taken up in a strictly Dectin-1-dependent manner to stimulate a mucosal and systemic antibody response. These findings are considered important for understanding gut immunity.
登录
查看更多内容
鼠伤寒沙门氏菌通过穿透和破坏佩耶斑块的专门上皮细胞来引起鼠的感染。
影响因子：
15.3
作者：
Jones, Bradley D.;Ghori, Nafisa;Falkow, Stanley
通讯作者：
Falkow, Stanley
DOI：
10.1073/pnas.96.6.3029
发表时间：
1999-03-16
影响因子：
11.1
作者：
Berdoz, J;Blanc, CT;Corthésy, B
通讯作者：
Corthésy, B
影响因子：
3.6
作者：
CLARK, MA;JEPSON, MA;HIRST, BH
通讯作者：
HIRST, BH
影响因子：
56.9
作者：
Kerneis, S;Bogdanova, A;Pringault, E
通讯作者：
Pringault, E
影响因子：
4.4
作者：
Boullier, Severine;Tanguy, Myriam;Phalipon, Armelle
通讯作者：
Phalipon, Armelle