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

Abstract

Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) expressed on a variety of DCs, is a C-type lectin receptor that recognizes glycans on a diverse range of pathogens, including parasites. The interaction of DC-SIGN with pathogens triggers specific signaling events that modulate DC-maturation and activity and regulate T-cell activation by DCs. In this work we evaluate whether F. hepatica glycans can immune modulate DCs via DC-SIGN. We demonstrate that DC-SIGN interacts with F. hepatica glycoconjugates through mannose and fucose residues. We also show that mannose is present in high-mannose structures, hybrid and trimannosyl N-glycans with terminal GlcNAc. Furthermore, we demonstrate that F. hepatica glycans induce DC-SIGN triggering leading to a strong production of TLR-induced IL-10 and IL-27p28. In addition, parasite glycans induced regulatory DCs via DC-SIGN that decrease allogeneic T cell proliferation, via the induction of anergic/regulatory T cells, highlighting the role of DC-SIGN in the regulation of innate and adaptive immune responses by F. hepatica. Our data confirm the immunomodulatory properties of DC-SIGN triggered by pathogen-derived glycans and contribute to the identification of immunomodulatory glyans of helminths that might eventually be useful for the design of vaccines against fasciolosis.

Human protein paucimannosylation: cues from the eukaryotic kingdoms

“…In turn, S. mansoni PMPs may be potent inducers of the mammalian immune system perhaps via an IgE‐mediated immune response during parasitic infections (van Remoortere et al ., ). Species within Fasciola , a genus of trematodes commonly known as liver flukes and also classified as flatworms, also express PMGs (Glycans #2a/b, #4, #10b, and #12) (Garcia‐Campos et al ., ; Rodríguez et al ., ). Interestingly, α‐fucosylated and α‐mannosylated epitopes of PMGs produced by Fasciola hepatica and other helminths are reportedly ligands of the immune‐modulatory dendritic cell‐specific intercellular adhesion molecule‐3‐grabbing non‐integrin (DC‐SIGN), a well‐studied C‐type lectin (van Die et al ., ; Meyer‐Wentrup et al ., ; Rodriguez et al ., 2017).…”

Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles

“…CLRs have also been suggested to associate with induction of Th2 responses by Toxocara -derived antigens ( 99 ). Among them, DC-SIGN is one of the most important receptors in recognition of T. canis, F. hepatica , and B. malayi -derived glycan products shaping the immune response toward a Th2/regulatory state ( 100 – 102 ). Rodríguez and colleagues have recently found that DC-SIGN plays a central role in priming Treg upon interaction with F. hepatica -derived glycans ( 102 ).…”

“…Among them, DC-SIGN is one of the most important receptors in recognition of T. canis, F. hepatica , and B. malayi -derived glycan products shaping the immune response toward a Th2/regulatory state ( 100 – 102 ). Rodríguez and colleagues have recently found that DC-SIGN plays a central role in priming Treg upon interaction with F. hepatica -derived glycans ( 102 ). The presence of mannose and fucose residues in F. hepatica -glycoconjugates can facilitate DC-SIGN stimulation and trigger intracellular pathway enabling DCs to prime Treg and inhibit proliferation of allogeneic T cells ( 102 ).…”

“…Rodríguez and colleagues have recently found that DC-SIGN plays a central role in priming Treg upon interaction with F. hepatica -derived glycans ( 102 ). The presence of mannose and fucose residues in F. hepatica -glycoconjugates can facilitate DC-SIGN stimulation and trigger intracellular pathway enabling DCs to prime Treg and inhibit proliferation of allogeneic T cells ( 102 ). Surprisingly, stimulation of DC-SIGN with F. hepatica -glycoconjugates activates a pathway in DCs which, during intracellular crosstalk with TLR-mediated signaling, induces IL-10 and IL-27 secretion in support of Treg expansion ( 102 ).…”

Characterization of dendritic cells and follicular dendritic cells in the hepatic lymph nodes and liver of sheep experimentally infected with Fasciola hepatica

“…More specifically, it has been reported that FhTeg induces DC modulation, resulting in a lack of T cell Th1 cytokine response and proliferation [21]. In addition, the glycan products produced by F. hepatica participate in the modulation of DC maturation and mediate the production of IL-10 and IL-4 during infection, inducing a Th2/regulatory-polarized immune response [22][23][24][25]. F. hepatica can also induce the development of phenotypes that are characterized by a decreased production of proinflammatory cytokines, as well as the expression of general markers that are characteristic of an M2 macrophage phenotype and have been shown to promote the differentiation of Th2 and Treg cells [26][27][28].…”