title: A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation.
abstract: Tolerance established by host-commensal interactions regulates host immunity at both local mucosal and systemic levels. The intestinal commensal strain Bacteroides fragilis elicits immune tolerance, at least in part, via the expression capsular polysaccharide A (PSA). How such niche-specific commensal microbial elements regulate extra-intestinal immune responses, as in the brain, remains largely unknown. We have recently shown that oral treatment with PSA suppresses neuro-inflammation elicited during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. This protection is dependent upon the expansion of immune-regulatory CD4 T cells (Treg) expressing CD39, an ectonucleotidase. Here, we further show that CD39 modulation of purinergic signals enhances migratory phenotypes of both total CD4 T cells and Foxp3(+) CD4 Tregs at central nervous system (CNS) lymphoid-draining sites in EAE in vivo and promotes their migration in vitro. These changes are noted during PSA treatment, which leads to heightened accumulation of CD39(+) CD4 Tregs in the CNS. Deficiency of CD39 abrogates accumulation of Treg during EAE, and is accompanied by elevated Th1/Th17 signals in the CNS and in gut-associated lymphoid tissues. Our results demonstrate that immune-modulatory commensal bacterial products impact the migratory patterns of CD4 Treg during CNS autoimmunity via the regulation of CD39. These observations provide clues as to how intestinal commensal microbiome is able to modulate Treg functions and impact host immunity in the distal site.
authors.affiliation: Department of Microbiology and Immunology; Geisel School of Medicine; Dartmouth College; Hanover, NH USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology; Geisel School of Medicine; Dartmouth College; Hanover, NH USA.
authors.forename: Sakhina
authors.initials: S
authors.lastname: Begum-Haque
authors.affiliation: 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.affiliation: Department of Microbiology and Immunology; Geisel School of Medicine; Dartmouth College; Hanover, NH 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, NH USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Christy
authors.affiliation: Department of Microbiology and Immunology; Geisel School of Medicine; Dartmouth College; Hanover, NH USA.
authors.forename: Eli J
authors.initials: EJ
authors.lastname: Kasper
authors.affiliation: Department of Microbiology and Immunobiology; Harvard Medical School; Boston, MA USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kasper
authors.affiliation: Division of Gastroenterology; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Department of Microbiology and Immunology; Geisel School of Medicine; Dartmouth College; Hanover, NH USA.
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Kasper
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001081:Apyrase / Q000032:analysis; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D001441:Bacteroides fragilis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D004195:Disease Models, Animal; D004679:Encephalomyelitis / Q000276:immunology / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D007108:Immune Tolerance; D008810:Mice, Inbred C57BL; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011135:Polysaccharides, Bacterial; D001081:Apyrase; C067869:CD39 antigen
keywords: EAE/MS; Th1/Th17; cell migration; commensal bacteria; ectonucleotidase; gut-brain axis; immuno-regulation; neuro-inflammation; regulatory T cells