Fasciola hepatica excretory-secretory products induce CD4+T cell anergy via selective up-regulation of PD-L2 expression on macrophages in a Dectin-1 dependent way

Guasconi, Lorena; Chiapello, Laura S.; Masih, Diana T.

doi:10.1016/j.imbio.2015.02.001

Cited by 24 publications

(30 citation statements)

References 31 publications

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“…It has been previously demonstrated that F. hepatica infection as well as ES released by the parasite induce AAM, which contributes to suppressing the Th1-type immune response and promoting Th2 development [9, 19]. In addition, it has been shown that PD-L2 expression in F. hepatica ES treated-macrophages is important in suppressing and inducing the secretion of IFN-γ and IL-10 by T cells, respectively [19].…”

Section: Resultsmentioning

confidence: 99%

“…During helminth infections, the suppression of T cell responses by PD-1 has been mostly attributed to macrophages expressing PD-L1 and /or PD-L2, and the PD-1 pathway has been shown to be an important mechanism of suppression by AAM [17, 18]. Related to this, it has recently been demonstrated that F. hepatica ES induce CD4+ T cell anergy via selective up-regulation of PD-L2 expression in macrophages [19]. Furthermore, blocking of PD-L2 in co-cultures of anti-CD3-stimulated CD4+ T cells with ES-treated macrophages increases IFN-γ and decreases IL-10 production [19].…”

Section: Introductionmentioning

confidence: 99%

“…Related to this, it has recently been demonstrated that F. hepatica ES induce CD4+ T cell anergy via selective up-regulation of PD-L2 expression in macrophages [19]. Furthermore, blocking of PD-L2 in co-cultures of anti-CD3-stimulated CD4+ T cells with ES-treated macrophages increases IFN-γ and decreases IL-10 production [19]. From these results, it appears that ES from F. hepatica might exert a control of the Th1-type response through PD-L2.…”

Section: Introductionmentioning

confidence: 99%

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PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

et al. 2016

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Macrophage plasticity is critical for controlling inflammation including those produced by helminth infections, where alternatively activated macrophages (AAM) are accumulated in tissues. AAM expressing the co-inhibitory molecule programmed death ligand 2 (PD-L2), which is capable of binding programmed death 1 (PD-1) expressed on activated T cells, have been demonstrated in different parasitic infections. However, the role of PD-L2 during F. hepatica infection has not yet been explored. We observed that F. hepatica infection or a F. hepatica total extract (TE) injection increased the expression of PD-L2 on peritoneal macrophages. In addition, the absence of PD-L2 expression correlated with an increase in susceptibility to F. hepatica infection, as evidenced by the shorter survival and increased liver damage observed in PD-L2 deficient (KO) mice. We assessed the contribution of the PD-L2 pathway to Th2 polarization during this infection, and found that the absence of PD-L2 caused a diminished Th2 type cytokine production by TE stimulated splenocytes from PD-L2 KO infected compared with WT mice. Besides, splenocytes and intrahepatic leukocytes from infected PD-L2 KO mice showed higher levels of IFN-γ than those from WT mice. Arginase expression and activity and IL-10 production were reduced in macrophages from PD-L2 KO mice compared to those from WT mice, revealing a strong correlation between PD-L2 expression and AAM polarization. Taken together, our data indicate that PD-L2 expression in macrophages is critical for AAM induction and the maintenance of an optimal balance between the Th1- and Th2-type immune responses to assure host survival during F. hepatica infection.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

et al. 2016

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“…In addition, MR was recently described to interact with F. hepatica molecules and to mediate the partial inhibition of TLR-induced maturation of bone marrow-derived DCs (59, 60), suggesting that the parasite targets more than one CLR to evade immunity. Indeed, other CLRs, such as MR and Dectin-1, have been reported to immunomodulate Arginase-1 and PDL-2 expression and TGFβ production by macrophages in response to F. hepatica excretory–secretory products (61, 62). …”

Section: Discussionmentioning

confidence: 99%

Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin

et al. 2017

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Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is a trematode zoonosis of interest in public health and livestock production. Like other helminths, F. hepatica modulates the host immune response by inducing potent polarized Th2 and regulatory T cell immune responses and by downregulating the production of Th1 cytokines. In this work, we show that F. hepatica glycans increase Th2 immune responses by immunomodulating TLR-induced maturation and function of dendritic cells (DCs). This process was mediated by the macrophage Gal/GalNAc lectin (MGL) expressed on DCs, which recognizes the Tn antigen (GalNAc-Ser/Thr) on parasite components. More interestingly, we identified MGL-expressing CD11c+ cells in infected animals and showed that these cells are recruited both to the peritoneum and the liver upon F. hepatica infection. These cells express the regulatory cytokines IL-10, TNFα and TGFβ and a variety of regulatory markers. Furthermore, MGL+ CD11c+ cells expand parasite-specific Th2/regulatory cells and suppress Th1 polarization. The results presented here suggest a potential role of MGL in the immunomodulation of DCs induced by F. hepatica and contribute to a better understanding of the molecular and immunoregulatory mechanisms induced by this parasite.

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“…GRAIL has been implicated in helminth infections previously, the expression of GRAIL following S.mansoni infection drives a form of T-cell anergy and silencing of this gene restores Th2 responsiveness [11] and high expression of this gene alone is enough to convert a naïve CD4 + T cell into an anergenic phenotype [38]. This is the first study to show that F. hepatica-released antigens can directly induce anergy, although a recent paper reported FhES to induce anergenic T cells, however the definition was based upon IL-10 secreting CD4 + T cells that express CTLA4 [39]. From our definition we would consider this to be a Treg rather than an anergenic T cell.…”

mentioning

confidence: 93%

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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Fasciola hepatica excretory-secretory products induce CD4+T cell anergy via selective up-regulation of PD-L2 expression on macrophages in a Dectin-1 dependent way

Cited by 24 publications

References 31 publications

PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin

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

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