title: Outer membrane vesicles of a human commensal mediate immune regulation and disease protection.
abstract: Commensal bacteria impact host health and immunity through various mechanisms, including the production of immunomodulatory molecules. Bacteroides fragilis produces a capsular polysaccharide (PSA), which induces regulatory T cells and mucosal tolerance. However, unlike pathogens, which employ secretion systems, the mechanisms by which commensal bacteria deliver molecules to the host remain unknown. We reveal that Bacteroides fragilis releases PSA in outer membrane vesicles (OMVs) that induce immunomodulatory effects and prevent experimental colitis. Dendritic cells (DCs) sense OMV-associated PSA through TLR2, resulting in enhanced regulatory T cells and anti-inflammatory cytokine production. OMV-induced signaling in DCs requires growth arrest and DNA-damage-inducible protein (Gadd45α). DCs treated with PSA-containing OMVs prevent experimental colitis, whereas Gadd45α(-/-) DCs are unable to promote regulatory T cell responses or suppress proinflammatory cytokine production and host pathology. These findings demonstrate that OMV-mediated delivery of a commensal molecule prevents disease, uncovering a mechanism of interkingdom communication between the microbiota and mammals.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Giardino Torchia
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Lawson
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
authors.forename: Sarkis K
authors.initials: SK
authors.lastname: Mazmanian
mesh_terms: D000818:Animals; D001441:Bacteroides fragilis / Q000276:immunology* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D055354:Exosomes / Q000276:immunology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000276:immunology; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D007155:Immunologic Factors; D009687:Nuclear Proteins; D011135:Polysaccharides, Bacterial; D051195:Toll-Like Receptor 2; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins