title: Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation.
abstract: Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-kappaB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-kappaB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naïve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-kappaB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis-fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-kappaB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-kappaB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Caitlin
authors.initials: C
authors.lastname: O'Mahony
authors.forename: Paul
authors.initials: P
authors.lastname: Scully
authors.forename: David
authors.initials: D
authors.lastname: O'Mahony
authors.forename: Sharon
authors.initials: S
authors.lastname: Murphy
authors.forename: Frances
authors.initials: F
authors.lastname: O'Brien
authors.forename: Anne
authors.initials: A
authors.lastname: Lyons
authors.forename: Graham
authors.initials: G
authors.lastname: Sherlock
authors.forename: John
authors.initials: J
authors.lastname: MacSharry
authors.forename: Barry
authors.initials: B
authors.lastname: Kiely
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.forename: Liam
authors.initials: L
authors.lastname: O'Mahony
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018988:Bacterial Translocation / Q000276:immunology; D001644:Bifidobacterium / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B