title: A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+)Foxp3(+) T cells and Treg function.
abstract: Polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis is a symbiosis factor that stimulates immunologic development within mammalian hosts. PSA rebalances skewed systemic T helper responses and promotes T regulatory cells (Tregs). However, PSA-mediated induction of Foxp3 in humans has not been reported. In mice, PSA-generated Foxp3(+) Tregs dampen Th17 activity thereby facilitating bacterial intestinal colonization while the increased presence and function of these regulatory cells may guard against pathological organ-specific inflammation in hosts. We herein demonstrate that PSA induces expression of Foxp3 along with CD39 among naïve CD4 T cells in vitro while promoting IL-10 secretion. PSA-activated dendritic cells are essential for the mediation of this regulatory response. When cultured with isolated Foxp3(+) Tregs, PSA enriched Foxp3 expression, enhanced the frequency of CD39(+)HLA-DR(+) cells, and increased suppressive function as measured by decreased TNFα expression by LPS-stimulated monocytes. Our findings are the first to demonstrate in vitro induction of human CD4(+)Foxp3(+) T cells and enhanced suppressive function of circulating Foxp3(+) Tregs by a human commensal bacterial symbiotic factor. Use of PSA for the treatment of human autoimmune diseases, in particular multiple sclerosis and inflammatory bowel disease, may represent a new paradigm in the approach to treating autoimmune disease.
authors.affiliation: a Department of Microbiology and Immunology ; Geisel School of Medicine; Dartmouth College ; Hanover , NH USA.
authors.forename: Kiel M
authors.initials: KM
authors.lastname: Telesford
authors.forename: Wang
authors.initials: W
authors.lastname: Yan
authors.forename: Javier
authors.initials: J
authors.lastname: Ochoa-Reparaz
authors.forename: Anudeep
authors.initials: A
authors.lastname: Pant
authors.forename: Christopher
authors.initials: C
authors.lastname: Kircher
authors.forename: Marc A
authors.initials: MA
authors.lastname: Christy
authors.forename: Sakhina
authors.initials: S
authors.lastname: Begum-Haque
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kasper
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Kasper
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D001081:Apyrase / Q000032:analysis; D001441:Bacteroides fragilis / Q000276:immunology* / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D016130:Immunophenotyping; D008070:Lipopolysaccharides / Q000276:immunology; D013559:Symbiosis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D008070:Lipopolysaccharides; C082161:lipopolysaccharide A; D001081:Apyrase; C067869:CD39 antigen
keywords: B. fragilis, Bacteroides fragilis; Bacteroides fragilis; DC, Dendritic cell; Foxp3; GF, Germ Free; MS, Multiple sclerosis; NCD4, Naïve CD4; PBMCs, Peripheral blood mononuclear cells; PSA, Polysaccharide A; SPF, Specific pathogen free; Sp1, Streptococcus pneumoniae polysaccharide type 1; T regulatory cells; Treg, T regulatory cell; ZPS, Zwitterionic polysaccharide.; autoimmunity; commensal microbiota; dendritic cell; ectonuclease; multiple sclerosis; pDC, Plasmacytoid dendritic cell; zwitterionic polysaccharide