title: Human dendritic cell activation by Neisseria meningitidis: phagocytosis depends on expression of lipooligosaccharide (LOS) by the bacteria and is required for optimal cytokine production.
abstract: Group B Neisseria meningitidis is a human pathogen, for which a universally effective vaccine is still not available. Immune responses to bacteria are initiated by dendritic cells (DC), which internalize and process bacterial antigens for presentation to T cells. We show here that optimal IL-12 and TNF-alpha production by human monocyte derived DC in response to killed serogroup B N. meningitidis depends on physical contact and internalization of the bacteria by DC. The majority of DC producing cytokines had internalized N. meningitidis while inhibition of bacterial internalization markedly impaired IL-12 and TNF-alpha, but not IL-6 production. Internalization of N. meningitidis was shown to depend on lipooligosaccharide (LOS) expressed by the bacteria with poor internalization of LOS deficient bacteria compared to wild-type bacteria. Restoration of LOS biosynthesis in a LOS regulatory strain also restored both internalization and cytokine production and was enhanced in the presence of LPS binding protein (LBP). These results suggest that DC phagocytosis depends on expression of LOS within the bacteria and that optimal cytokine production, particularly IL-12, requires internalization of the bacteria. These findings have important implications for designing vaccines that will induce protective immune responses to group B N. meningitidis.
authors.affiliation: Immunobiology Unit, Institute of Child Health, UCL, London UK. h.uronen@ich.ucl.ac.uk
authors.forename: Heli
authors.initials: H
authors.lastname: Uronen-Hansson
authors.forename: Liana
authors.initials: L
authors.lastname: Steeghs
authors.forename: Jennifer
authors.initials: J
authors.lastname: Allen
authors.forename: Garth L J
authors.initials: GL
authors.lastname: Dixon
authors.forename: Mohamed
authors.initials: M
authors.lastname: Osman
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
authors.forename: Simon Y C
authors.initials: SY
authors.lastname: Wong
authors.forename: Robin
authors.initials: R
authors.lastname: Callard
authors.forename: Nigel
authors.initials: N
authors.lastname: Klein
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008589:Meningococcal Infections / Q000382:microbiology; D038541:Neisseria meningitidis, Serogroup B / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; D018664:Interleukin-12