title: Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut.
abstract: The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.
authors.affiliation: Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada.
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Fritz
authors.forename: Olga Lucia
authors.initials: OL
authors.lastname: Rojas
authors.forename: Nathalie
authors.initials: N
authors.lastname: Simard
authors.forename: Douglas D
authors.initials: DD
authors.lastname: McCarthy
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hapfelmeier
authors.forename: Stephen
authors.initials: S
authors.lastname: Rubino
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.forename: Mani
authors.initials: M
authors.lastname: Larijani
authors.forename: Jean
authors.initials: J
authors.lastname: Gosselin
authors.forename: Ivaylo I
authors.initials: II
authors.lastname: Ivanov
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Macpherson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D019070:Cell Lineage; D002478:Cells, Cultured; D002678:Chimera / Q000276:immunology; D044082:Citrobacter rodentium / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D005856:Germ-Free Life; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D007421:Intestine, Small / Q000166:cytology* / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D010641:Phenotype; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology / Q000378:metabolism
chemical_list: D007070:Immunoglobulin A; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse