title: An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling.
abstract: The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. The intestinal microbiome can influence host susceptibility to extra-intestinal autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for the human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through Toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39(+) CD4 T-cell subset by PSA. Ablation of CD39 signalling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3(+) CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Kiel M
authors.initials: KM
authors.lastname: Telesford
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Ochoa-Repáraz
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Sakhina
authors.initials: S
authors.lastname: Haque-Begum
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Christy
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Eli J
authors.initials: EJ
authors.lastname: Kasper
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kasper
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Kasper
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000235:genetics / Q000378:metabolism*; D001441:Bacteroides fragilis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis; D011135:Polysaccharides, Bacterial / Q000378:metabolism*; D015398:Signal Transduction; D013559:Symbiosis; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011135:Polysaccharides, Bacterial; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D001081:Apyrase; C067869:CD39 antigen