Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway
| Autor: | Grainger, Smith, KA, Hewitson, JP, McSorley, HJ, Harcus, Y, Filbey, KJ, Finney, CAM, Greenwood, EJD, Knox, DP, Wilson, MS, Belkaid, Y, Rudensky, AY, Maizels, RM |
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| Předmět: |
chemical and pharmacologic phenomena
Mice Transgenic Dioxoles Smad2 Protein Protein Serine-Threonine Kinases T-Lymphocytes Regulatory Host-Parasite Interactions Mice Th2 Cells Transforming Growth Factor beta parasitic diseases Animals Smad3 Protein Phosphorylation Cell Proliferation Strongylida Infections Mice Inbred BALB C Nematospiroides dubius Receptor Transforming Growth Factor-beta Type II hemic and immune systems Forkhead Transcription Factors Th1 Cells 3. Good health Gene Expression Regulation Antigens Helminth Benzamides Chronic Disease biological phenomena cell phenomena and immunity Receptors Transforming Growth Factor beta Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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