Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-ß pathway.
J Exp Med
; 207(11): 2331-41, 2010 Oct 25.
Article
em En
| MEDLINE
| ID: mdl-20876311
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 Foxp3â» 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 Foxp3â» 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) ß receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-ßRII cells and was abolished by the TGF-ß 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-ß did not recognize HES, whereas antisera that inhibited HES did not affect TGF-ß. 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.
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Base de dados:
MEDLINE
Assunto principal:
Nematospiroides dubius
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Transdução de Sinais
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Regulação da Expressão Gênica
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Fator de Crescimento Transformador beta
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Infecções por Strongylida
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Linfócitos T Reguladores
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Fatores de Transcrição Forkhead
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Antígenos de Helmintos
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article