title: Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway.
abstract: Foxp3-expressing regulatory T (T reg) cells have been implicated in parasite-driven inhibition of host immunity during chronic infection. We addressed whether parasites can directly induce T reg cells. Foxp3 expression was stimulated in naive Foxp3⁻ T cells in mice infected with the intestinal helminth Heligmosomoides polygyrus. In vitro, parasite-secreted proteins (termed H. polygyrus excretory-secretory antigen [HES]) induced de novo Foxp3 expression in fluorescence-sorted Foxp3⁻ splenocytes from Foxp3-green fluorescent protein reporter mice. HES-induced T reg cells suppressed both in vitro effector cell proliferation and in vivo allergic airway inflammation. HES ligated the transforming growth factor (TGF) β receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-βRII cells and was abolished by the TGF-β signaling inhibitor SB431542. This inhibitor also reduced worm burdens in H. polygyrus-infected mice. HES induced IL-17 in the presence of IL-6 but did not promote Th1 or Th2 development under any conditions. Importantly, antibody to mammalian TGF-β did not recognize HES, whereas antisera that inhibited HES did not affect TGF-β. Foxp3 was also induced by secreted products of Teladorsagia circumcincta, a related nematode which is widespread in ruminant animals. We have therefore identified a novel pathway through which helminth parasites may stimulate T reg cells, which is likely to be a key part of the parasite's immunological relationship with the host.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, Scotland, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Grainger
authors.forename: Katie A
authors.initials: KA
authors.lastname: Smith
authors.forename: James P
authors.initials: JP
authors.lastname: Hewitson
authors.forename: Henry J
authors.initials: HJ
authors.lastname: McSorley
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Harcus
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Filbey
authors.forename: Constance A M
authors.initials: CA
authors.lastname: Finney
authors.forename: Edward J D
authors.initials: EJ
authors.lastname: Greenwood
authors.forename: David P
authors.initials: DP
authors.lastname: Knox
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D004149:Dioxoles / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006790:Host-Parasite Interactions / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009351:Nematospiroides dubius / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051899:Smad2 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000947:Antigens, Helminth; D001549:Benzamides; D004149:Dioxoles; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II