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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Helminth / immunology*
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Antigens, Helminth / metabolism
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Benzamides / pharmacology
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Cell Proliferation / drug effects
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Chronic Disease
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Dioxoles / pharmacology
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Forkhead Transcription Factors / biosynthesis
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Host-Parasite Interactions / drug effects
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Host-Parasite Interactions / genetics
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Host-Parasite Interactions / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Nematospiroides dubius / immunology*
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Nematospiroides dubius / metabolism
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Phosphorylation / genetics
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Phosphorylation / immunology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / immunology
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Smad2 Protein / genetics
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Smad2 Protein / immunology
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / immunology
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Smad3 Protein / metabolism
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Strongylida Infections / genetics
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Strongylida Infections / immunology*
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Strongylida Infections / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology*
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Transforming Growth Factor beta / metabolism
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Antigens, Helminth
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Benzamides
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Dioxoles
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Smad2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II