Kim Donghyun, Kim Yun-Gi, Seo Sang-Uk, Kim Dong-Jae, Kamada Nobuhiko, Prescott Dave, Chamaillard Mathias, Philpott Dana J, Rosenstiel Philip, Inohara Naohiro, Núñez Gabriel
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Nat Med. 2016 May;22(5):524-30. doi: 10.1038/nm.4075. Epub 2016 Apr 11.
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 and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (TFH) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by Itgax) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with Staphylococcus sciuri, which has 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 dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.
霍乱毒素（CT）是诱导黏膜免疫反应的一种强效佐剂。然而，CT诱导佐剂活性的机制仍不清楚。在此我们表明，微生物群对于鼻内免疫后诱导抗原特异性IgG产生至关重要。用CT进行黏膜疫苗接种后，经抗生素处理的小鼠和无菌（GF）小鼠的抗原特异性IgG量均减少，回忆刺激的细胞因子反应较小，滤泡辅助性T（TFH）细胞反应受损，浆细胞数量减少。CT的佐剂活性需要通过表达整合素CD11c（由Itgax编码）的细胞中的含核苷酸结合寡聚化结构域2（Nod2）传感器识别共生细菌。用Nod2激动剂重建GF小鼠或用具有高Nod2刺激活性的松鼠葡萄球菌进行单一定殖，足以促进强大的CT佐剂活性，而具有低Nod2刺激活性的细菌则不能。从机制上讲，CT通过细胞内环磷酸腺苷增强树突状细胞中Nod2介导的细胞因子产生。这些结果表明微生物群和细胞内受体Nod2在促进CT的黏膜佐剂活性中发挥作用。
