Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature. 2013 Feb 7;494(7435):116-20. doi: 10.1038/nature11809. Epub 2013 Jan 13.
The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX(3)CR1(hi) mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory. These findings define a central role for commensals in regulating the migration to the MLNs of CX(3)CR1(hi) mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.
肠道微生物群在免疫系统和代谢稳态中起着关键作用，但它必须被宿主耐受，以避免炎症反应，否则炎症反应会破坏将宿主与腔内容物分开的上皮屏障。这种调节的破坏以及对共生菌的不当免疫反应被认为导致了炎症性肠病，如克罗恩病和溃疡性结肠炎的发展。我们提出，肠道免疫系统受到微生物群的指导，以限制对腔抗原的反应。在这里，我们在小鼠中证明，在稳定状态下，微生物群抑制共生菌和致病菌从腔内向关键免疫诱导部位肠系膜淋巴结（MLN）的转运。然而，在缺乏 Myd88 或在抗生素诱导的生态失调的情况下，非侵入性细菌以 CCR7 依赖性方式被运送到 MLN，并诱导 T 细胞反应和 IgA 产生。运输是由 CX(3)CR1(hi)单核吞噬细胞完成的，先前报道这种肠道细胞群没有迁移能力。这些发现定义了共生菌在调节 CX(3)CR1(hi)单核吞噬细胞向 MLN 迁移中的核心作用，这些细胞具有捕获腔细菌的能力，从而将肠道免疫反应分隔开来，以避免炎症。
