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The trematode Fasciola hepatica is responsible for chronic zoonotic infection globally. Despite causing a potent T-helper 2 response, it is believed that potent immunomodulation is responsible for rendering this host reactive non-protective host response thereby allowing the parasite to remain long-lived. We have previously identified a growth factor, FhTLM, belonging to the TGF superfamily can have developmental effects on the parasite. Herein we demonstrate that FhTLM can exert influence over host immune functions in a host receptor specific fashion. FhTLM can bind to receptor members of the Transforming Growth Factor (TGF) superfamily, with a greater affinity for TGF-β RII. Upon ligation FhTLM initiates the Smad2/3 pathway resulting in phenotypic changes in both fibroblasts and macrophages. The formation of fibroblast CFUs is reduced when cells are cultured with FhTLM, as a result of TGF-β RI kinase activity. In parallel the wound closure response of fibroblasts is also delayed in the presence of FhTLM. When stimulated with FhTLM blood monocyte derived macrophages adopt an alternative or regulatory phenotype. They express high levels interleukin (IL)-10 and arginase-1 while displaying low levels of IL-12 and nitric oxide. Moreover they also undergo significant upregulation of the inhibitory receptor PD-L1 and the mannose receptor. Use of RNAi demonstrates that this effect is dependent on TGF-β RII and mRNA knock-down leads to a loss of IL-10 and PD-L1. Finally, we demonstrate that FhTLM aids newly excysted juveniles (NEJs) in their evasion of antibody-dependent cell cytotoxicity (ADCC) by reducing the NO response of macrophages—again dependent on TGF-β RI kinase. FhTLM displays restricted expression to the F. hepatica gut resident NEJ stages. The altered fibroblast responses would suggest a role for dampened tissue repair responses in facilitating parasite migration. Furthermore, the adoption of a regulatory macrophage phenotype would allow for a reduced effector response targeting juvenile parasites which we demonstrate extends to an abrogation of the ADCC response. Thus suggesting that FhTLM is a stage specific evasion molecule that utilises host cytokine receptors. These findings are the first to clearly demonstrate the interaction of a helminth cytokine with a host receptor complex resulting in immune modifications that facilitate the non-protective chronic immune response which is characteristic of F. hepatica infection., Author Summary Parasitic worms, helminths, can cause long-lived chronic infection in many hosts that they infection. The liver fluke, Fasciola hepatica, is one such parasite causing global infection of both humans and animals. F. hepatica exerts an influence over the immune system such that it avoids effector mechanisms and prevents the development of effective immunity. Here we characterise a molecule—FhTLM—derived from juvenile parasites that is similar to the regulatory cytokine TGF-β. We show that FhTLM will bind to host TGF-β receptors with a reduced affinity when compared with mammalian TGF-β. Despite this FhTLM can induce Smad2/3 signalling in host leukocytes, which is key to initiating gene transcription. Phenotypically FhTLM causes fibroblasts to slow their growth and replication response resulting in slower wound healing. Importantly FhTLM induces a macrophage phenotype that resembles a regulatory macrophage phenotype identified in other species undergoing helminth infection. Finally we Our work highlights the potential of FhTLM to play important roles in controlling host immunity when initially infected with juvenile parasites, thereby preventing the development of effective immunity.