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

Abstract

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...

Fasciola hepatica glycoconjugates immuneregulate dendritic cells through the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin inducing T cell anergy

“…Furthermore, H. pylori glycans that interact with DC-SIGN induced tolerogenic DCs that failed to induce T cell effector functions but induced regulatory T cells45. In the context of F. hepatica immunoregulatory properties, other CLRs can also participate in the induction of T cell anergy as has been recently proposed for the MR on bone marrow-derived DCs induced anergic-like T cells via DCs, although only a small reduction of T cell anergy was found when using DCs from knock-out mice, suggesting that other CLRs can participate in this process33. Furthermore, this process did not seem to be mediated by recognition of parasite glycoconjugates by the MR on BMDCs but the MR interacting with CD4 + T cells33.…”

“…Very recent reports3334, including our own32, have brought insights about the role of F. hepatica glycans in mediating the regulation of DC-maturation through CLR recognition. Our group has recently described that glycan structures produced by F. hepatica participate in the modulation of bone marrow-derived DCs (BMDCs) and induce/mediate the production of IL-10 and IL-4 during infection32.…”

“…Moreover, mannose inhibition indicated that a mannose-specific receptor mediates the recognition of F. hepatica glycans by DCs32. More recently, the mannose receptor was found to mediate parasite tegumental glycan recognition by BMDCs3334, although further experiments suggested that also other mannose-specific CLRs are participating in F. hepatica modulation of DCs34. Last, a MR-dependent mechanism of inducing T cell anergy by DCs loaded with parasite tegumental molecules was reported33.…”

“…More recently, the mannose receptor was found to mediate parasite tegumental glycan recognition by BMDCs3334, although further experiments suggested that also other mannose-specific CLRs are participating in F. hepatica modulation of DCs34. Last, a MR-dependent mechanism of inducing T cell anergy by DCs loaded with parasite tegumental molecules was reported33. Yet, molecular mechanisms associated to the modulation of human DC function by F. hepatica are scarce.” Thus, we sought to evaluate whether F. hepatica glycoconjugates interact with DC-SIGN and whether this interaction regulates the stimulatory function of DCs by evaluating their capacity to induce regulatory or anergic T cells.…”

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

“…This enhanced uptake could favor antigen presentation and the activation of specific CD4 + T cells (58). 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).…”