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

Grainger, John; Smith, Katie; Hewitson, James P.; McSorley, Henry J.; Harcus, Yvonne; Filbey, Kara J.; Finney, Constance A. M.; Greenwood, Edward Jd; Knox, David P.; Wilson, Mark S.; Belkaid, Yasmine; Rudensky, Alexander Y.; Maizels, Rick M.

doi:10.1083/jcb1911oia3

Cited by 68 publications

(109 citation statements)

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“…The induction of CD103 is considered an activation marker for Tregs 46 and is strongly TGF‐β‐dependent in H. polygyrus ‐infected mice 45 . Furthermore, interfering with TGF‐β signaling in chronically infected mice has been shown to increase worm expulsion, 22 although depletion of Tregs in Foxp3–diphtheria toxin receptor mice did not alter the worm burden at day 14 47 …”

Section: Resultsmentioning

confidence: 99%

“…Thus, blocking IFN‐γ responses enables a susceptible mouse to clear infection, 9 whereas exogenous IL‐12 prolongs infection in a genotypically resistant animal 17 . A further layer of complexity is observed with the duodenal parasite Heligmosomoides polygyrus , which generates a significant regulatory T‐cell population that inhibits Th2 immunity 18 , 19 , 20 , 21 , 22 . Recent data implicate similar regulatory effects in human intestinal helminth infections, 23 , 24 , 25 , 26 suggesting that H. polygyrus may offer a valuable system to model such interactions.…”

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confidence: 99%

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Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection

et al. 2014

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The nematode Heligmosomoides polygyrus is an excellent model for intestinal helminth parasitism. Infection in mice persists for varying lengths of time in different inbred strains, with CBA and C57BL/6 mice being fully susceptible, BALB/c partially so and SJL able to expel worms within 2–3 weeks of infection. We find that resistance correlates not only with the adaptive Th2 response, including IL-10 but with activation of innate lymphoid cell and macrophage populations. In addition, the titer and specificity range of the serum antibody response is maximal in resistant mice. In susceptible strains, Th2 responses were found to be counterbalanced by IFN-γ-producing CD4+ and CD8+ cells, but these are not solely responsible for susceptibility as mice deficient in either CD8+ T cells or IFN-γ remain unable to expel the parasites. Foxp3+ Treg numbers were comparable in all strains, but in the most resistant SJL strain, this population does not upregulate CD103 in infection, and in the lamina propria the frequency of Foxp3+CD103+ T cells is significantly lower than in susceptible mice. The more resistant SJL and BALB/c mice develop macrophage-rich IL-4Rα-dependent Type 2 granulomas around intestinal sites of larval invasion, and expression of alternative activation markers Arginase-1, Ch3L3 (Ym1) and RELM-α within the intestine and the peritoneal lavage was also strongly correlated with helminth elimination in these strains. Clodronate depletion of phagocytic cells compromises resistance of BALB/c mice and slows expulsion in the SJL strain. Thus, Type 2 immunity involves IL-4Rα-dependent innate cells including but not limited to a phagocyte population, the latter likely involving the action of specific antibodies.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection

et al. 2014

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“…Helminth parasites can survive within their hosts for many years by suppressing T-cell driven protective immune responses and Th1/Th2-mediated pathology through the induction of regulatory networks that suppress inflammatory responses [1][2][3][4]. These regulatory networks include regulatory T cells (Treg) that in the context of helminth infection is widely understood.…”

Section: Introductionmentioning

confidence: 99%

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

Aldridge

O’Neill

2016

Eur J Immunol

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FoxP3 + Treg cells and anergic T cells are the two regulatory phenotypes of T-cell responses associated with helminth infection. Here, we examine the T-cell responses in mice duringKeywords: Anergy r C-type lectin receptors r Dendritic cells r Helminth infection r Host-pathogen interactions r Mannose receptor r T-cell responses Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHelminth parasites can survive within their hosts for many years by suppressing T-cell driven protective immune responses and Th1/Th2-mediated pathology through the induction of regulatory networks that suppress inflammatory responses [1][2][3][4]. These regulatory networks include regulatory T cells (Treg) that in the context of helminth infection is widely understood. Treg cells supCorrespondence: Dr. Sandra M. O'Neill e-mail: sandra.oneill@dcu.ie press the immune response to helminth-driven Th1/Th2 immune pathology through the induction of IL-10 and TGF-β. Brugia malayi, infection induces a regulatory response with enhanced FoxP3 expression and increased cell surface expression of CTLA4, a negative regulator of T-cell function [5] while Schistosoma haematobium infection in humans has also been associated with FoxP3 + Treg cells with the highest percentage of this cell population observed in younger patients [6]. However, less is currently known about the regulatory response termed in vivo anergy or adaptive tolerance.Few studies have examined the role of anergenic T cells during helminth infection. The induction of this cell population is thought C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1180-1192 Immunity to infection 1181 to be the result of the persistent contact of parasite antigen with immune cells during chronic helminth infection [7]. Anergenic T cells differ from Treg cells in that they do not express FoxP3 or produce IL-10 or TGF-β. Instead anergy is a hyporesponsive state with the failure of T cells to proliferate or produce cytokines when restimulated with antigens in vitro [8]. Anergic T cells do not secrete IL-2, a factor important for T-cell proliferation and effector responses. However, the addition of IL-2 can overcome this hyporesponsiveness, restoring helminth-driven T-cell responses. Gene analysis studies have identified a number of genes including Rnf128 (Grail), Itch, Egr2 and Egr3, and CblB that are involved in the induction and maintenance of T-cell anergy [9,10]. A number of helminth infections have shown T-cell anergy or Tcell hyporesponsiveness to be involved in immune suppression. Studies involving S. mansoni show the enhanced expression of GRAIL is linked to the suppression of Th2 cells and also using a filarial nematode, CD4 + T cells become functionally unresponsive [11,12]. Other studies indicate that anergenic-like T cells are the result of helminth infections, with an increase in anergenic markers and T-cell suppression [13][14][15][16]. Fasciola hepatica causes chronic liver d...

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“…To block endogenous TGF-β, 5 μM SB-431542 (ALK5 inhibitor; Sigma-Aldrich) was added to the culture 1 h before adding peptides. After 4 or 7 days, cells were stained for Foxp3 in CD4 + CD25 + -T-gated cells in case of the cultures of CD90 + T cells and DCs or in CD4 + -gated cells for cultures of splenocytes [14, 15]. …”

Section: Methodsmentioning

confidence: 99%

The Histone Peptide H471–94 Alone Is More Effective than a Cocktail of Peptide Epitopes in Controlling Lupus: Immunoregulatory Mechanisms

et al. 2011

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Tolerance therapy with nucleosomal histone peptides H4 , H4 16-39 , or H1′ 22-42 controls disease in lupus-prone SNF1 mice. It would be clinically important to determine whether a cocktail of the above epitopes would be superior. Herein, we found that compared with cocktail peptides, H4 71-94 monotherapy more effectively delayed nephritis onset, prolonged lifespan, diminished immunoglobulin G autoantibody levels, reduced autoantigen-specific Th1 and Th17 responses and frequency of T FH cells in spleen and the helper ability of autoimmune T cells to B cells, by inducing potent CD8 Treg cells. H4 71-94 therapy was superior in "tolerance spreading," suppressing responses to other autoepitopes, nucleosomes, and ribonucleoprotein. We also developed an in vitro assay for therapeutic peptides (potentially in humans), which showed that H4 71-94 , without exogenous transforming growth factor (TGF)-β, was efficient in inducing stable CD4 + CD25 + Foxp3 + T cells by decreasing interleukin 6 and increasing TGF-β production by dendritic cells that induced ALK5-dependent Smad-3 phosphorylation (TGF-β signal) in target autoimmune CD4 + T cells.

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

Cited by 68 publications

References 1 publication

Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection

Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

The Histone Peptide H471–94 Alone Is More Effective than a Cocktail of Peptide Epitopes in Controlling Lupus: Immunoregulatory Mechanisms

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