Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells
Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells
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DOI：
10.1038/nature06033
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发表时间：
2007-08-23
期刊：
影响因子：
64.8
通讯作者：
Ohteki, Toshiaki
中科院分区：
文献类型：
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作者：
Tezuka, Hiroyuki;Abe, Yukiko;Ohteki, Toshiaki
免疫球蛋白-A在粘膜防御感染性微生物方面具有不可替代的作用（1-6）。在人类和小鼠中，产生IgA的浆细胞约占外周淋巴组织总浆细胞的20%，而粘膜相关淋巴组织（MALT）中超过80%的浆细胞产生伊加（1-6）。免疫学中最重要的生物学问题之一是为什么这种“偏向性”的伊加合成发生在MALT而不是其他淋巴器官。在这里，我们表明，伊加类转换重组（CSR）在诱导型一氧化氮合酶缺陷（iNOS（-/-）;基因也称为Nos 2）小鼠受损。iNOS通过表达转化生长因子β受体调节T细胞依赖性IgA CSR，并通过产生增殖诱导配体（APRIL，也称为Tnfsf 13）和肿瘤坏死因子（TNF）家族的B细胞活化因子（BAFF，也称为Tnfsf 13 b）调节T细胞非依赖性伊加CSR。值得注意的是，iNOS优先表达在MALT树突状细胞中，以响应Toll样受体对大肠杆菌的识别。此外，iNOS（+）树突状细胞的过继转移挽救了iNOS（-/-）小鼠中伊加产生。进一步的分析显示，MALT树突细胞是一种产生TNF-α/iNOS的树突细胞亚群，最初在感染单核细胞增生李斯特菌的小鼠中鉴定（7，8）。天然存在的产生TNF-α/iNOS的树突状细胞亚群的存在可以解释MALT中伊加产生的优势，这对肠道稳态至关重要。
Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes(1-6). In human and mouse, IgA-producing plasma cells comprise similar to 20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT)(1-6). One of the most biologically important and long-standing questions in immunology is why this 'biased' IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient (iNOS(-/-); gene also called Nos2) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-beta receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll-like receptor. Furthermore, adoptive transfer of iNOS(+) dendritic cells rescues IgA production in iNOS(-/-) mice. Further analysis revealed that the MALT dendritic cells are a TNF-alpha/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes(7,8). The presence of a naturally occurring TNF-alpha/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis.