Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin.
Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin.
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DOI：
10.1038/nm.4075
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发表时间：
2016-05
期刊：
影响因子：
82.9
通讯作者：
Núñez G
中科院分区：
文献类型：
--
作者：
Kim D;Kim YG;Seo SU;Kim DJ;Kamada N;Prescott D;Chamaillard M;Philpott DJ;Rosenstiel P;Inohara N;Núñez G
霍乱毒素(CT)是一种诱导粘膜免疫反应的强佐剂。然而，CT诱导佐剂活性的机制仍不清楚。在这里，我们表明，微生物群是关键的诱导抗原特异性的免疫球蛋白产生后，鼻腔免疫。CT黏膜免疫后，抗生素处理组和无菌(GF)组均出现抗原特异性免疫球蛋白G降低，细胞因子反应增强，滤泡辅助性T细胞(TFH)反应减弱，浆细胞减少。CT的佐剂作用需要通过CD11c+细胞中的NOD2识别共生菌。用NOD2激动剂或具有高NOD2刺激活性的坐骨神经葡萄球菌重组GF小鼠足以促进强大的CT佐剂活性，而低NOD2刺激活性的细菌则不能。机制上，CT通过细胞内cAMP促进NOD2介导的DC细胞因子的产生。这些结果表明，微生物区系和胞内受体NOD2在促进CT的黏膜佐剂活性方面具有重要作用。
Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated mice and germ-free (GF) had reduced antigen-specific IgG, recall-stimulated cytokine responses, an impaired follicular helper T (TFH) response and reduced plasma cells. Recognition of symbiotic bacteria via Nod2 in CD11c+ cells was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or Staphylococcus sciuri having high Nod2-stimulatory activity was sufficient to promote robust CT adjuvant activity whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in DCs via intracellular cAMP. These results show an important role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.