| 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. © 2010 Grainger et al. |
| Keywords: |
signal transduction; controlled study; protein expression; protein phosphorylation; nonhuman; protein function; transcription factor foxp3; cell proliferation; forkhead transcription factors; animal cell; mouse; animals; mice; animal tissue; smad2 protein; smad3 protein; transforming growth factor beta; interleukin 7; animal experiment; animal model; in vivo study; in vitro study; phosphorylation; mice, inbred balb c; mice, transgenic; chronic disease; gene expression regulation; regulatory t lymphocyte; antigen; t-lymphocytes, regulatory; protein-serine-threonine kinases; interleukin 6; transforming growth factor beta receptor; protein secretion; receptors, transforming growth factor beta; 4 [4 (1,3 benzodioxol 5 yl) 5 (2 pyridinyl) 1h imidazol 2 yl]benzamide; gene induction; immunity; th2 cells; benzamides; th1 cells; heligmosomoides polygyrus; helminthiasis; respiratory tract inflammation; antigens, helminth; dioxoles; host-parasite interactions; nematospiroides dubius; strongylida infections
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