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Microbiota Restrict Trafficking of Bacteria to Mesenteric Lymph Nodes by CX3CR1 Cells

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 (Impact Factor: 42.35). 01/2013; 494(7435). DOI: 10.1038/nature11809
Source: PubMed

ABSTRACT 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.

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    • "Mucosal DCs constitutively express a chemokine receptor CCR7 that guides them to the mesenteric lymph nodes (MLNs) that drain the gut to present intestinal antigens to T cells (Bogunovic et al., 2006; Jaensson et al., 2008; Johansson-Lindbom et al., 2005; Schulz et al., 2009). In contrast to DCs, steady state CCR7 − mucosal Mϕs are stationary (MLNnonmigratory ) (Bogunovic et al., 2009; Diehl et al., 2013; Schulz et al., 2009), highly phagocytic cells (Niess et al., 2005; Rivollier et al., 2012) that are thought to be essential for maintaining tissue homeostasis and inducing innate immune responses but playing only a secondary role in adaptive immune responses (Hadis et al., 2011; Mazzini et al., 2014; Schreiber et al., 2013). Mϕs derive from Gr1 hi monocytes and their development is regulated by CSF1 and CSF1R (Bain et al., 2014; Bogunovic et al., 2009; Varol et al., 2009). "
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    DESCRIPTION: Abstract Mononuclear phagocytes are essential for protecting against pathogens breaching the intestinal mucosa and maintaining the integrity of the gastrointestinal tract. The mononuclear phagocyte family of the healthy intestine is represented by a small population of hematopoietic cells including dendritic cells and macrophages. Distinct mononuclear phagocyte subsets strategically accumulate within and below the mucosal epithelium and are distributed in the submucosa and muscularis externa. Shaped by its unique microenvironment, each mononuclear phagocyte subset is developmentally and functionally unique and phenotypically distinct. Here we summarize our recent advances on identifying and purifying various intestinal mononuclear phagocyte subsets by flow cytometry in the context of their developmental properties and location within the intestinal tissue.
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    • "Mucosal DCs constitutively express a chemokine receptor CCR7 that guides them to the mesenteric lymph nodes (MLNs) that drain the gut to present intestinal antigens to T cells (Bogunovic et al., 2006; Jaensson et al., 2008; Johansson-Lindbom et al., 2005; Schulz et al., 2009). In contrast to DCs, steady state CCR7 − mucosal Mϕs are stationary (MLNnonmigratory ) (Bogunovic et al., 2009; Diehl et al., 2013; Schulz et al., 2009), highly phagocytic cells (Niess et al., 2005; Rivollier et al., 2012) that are thought to be essential for maintaining tissue homeostasis and inducing innate immune responses but playing only a secondary role in adaptive immune responses (Hadis et al., 2011; Mazzini et al., 2014; Schreiber et al., 2013). Mϕs derive from Gr1 hi monocytes and their development is regulated by CSF1 and CSF1R (Bain et al., 2014; Bogunovic et al., 2009; Varol et al., 2009). "
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