Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway

TY - JOUR

T1 - Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway

AU - Grainger, John R

AU - Smith, Katie A

AU - Hewitson, James P

AU - McSorley, Henry J

AU - Harcus, Yvonne

AU - Filbey, Kara J

AU - Finney, Constance A M

AU - Greenwood, Edward J D

AU - Knox, David P

AU - Wilson, Mark S

AU - Belkaid, Yasmine

AU - Rudensky, Alexander Y

AU - Maizels, Rick M

PY - 2010/10/25

Y1 - 2010/10/25

N2 - 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.

AB - 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.

KW - Animals

KW - Antigens, Helminth

KW - Benzamides

KW - Cell Proliferation

KW - Chronic Disease

KW - Dioxoles

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation

KW - Host-Parasite Interactions

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Transgenic

KW - Nematospiroides dubius

KW - Phosphorylation

KW - Protein-Serine-Threonine Kinases

KW - Receptors, Transforming Growth Factor beta

KW - Signal Transduction

KW - Smad2 Protein

KW - Smad3 Protein

KW - Strongylida Infections

KW - T-Lymphocytes, Regulatory

KW - Th1 Cells

KW - Th2 Cells

KW - Transforming Growth Factor beta

U2 - 10.1084/jem.20101074

DO - 10.1084/jem.20101074

M3 - Article

C2 - 20876311

SN - 0022-1007

VL - 207

SP - 2331

EP - 2341

JO - The Journal of experimental medicine

JF - The Journal of experimental medicine

IS - 11

ER -