Abstract
Fasciola hepatica infection of ruminants leads to non-resolving chronic infection, as patency develops, there is switching to a TGF-β and IL-10 led response. Here, we explore the responses of CD4 T-cells within the major draining lymph nodes. We found minimal expression of Foxp3 within CD4 cells but elevated levels within the γδ (WC1+) population. There is a strong T-cell-intrinsic exhaustion phenotype within the hepatic lymph node (HLN) characterized by a lack of antigen-specific proliferation and cytokine secretion. CD4 T-cells recovered from the HLN had high levels of PD-1 expression and low levels of IL-2 secretion. Exogenous IL-2 partially rescued this defect; when combined with neutralization of IL-10 and TGF-β, full restoration of proliferation, and cytokine production was achieved. Moreover, there is a clear uncoupling of the mechanisms that facilitate this regulation with parasite-specific proliferation and cytokine secretion being governed by independent means. These data would suggest that there is a CD4 T-cell-intrinsic regulation in place early in chronic infection, potentially leading to failure in resistance to reinfection.
Highlights
Fasciola hepatica is known to establish chronic infections in its bovine host despite the development of a strong type-2/CD4+ Th2 response [1]
In the bovine model of infection, we have previously shown at a peripheral level, that both TGF-β and IL-10 played a role in limiting IL-4 and IFN-γ production
Escamilla et al [19] have shown in goats and sheep that there is no expansion of CD4+Foxp3+ cells by 9 days of infection but, by 15–19 weeks of postinfection, an infiltrate of these cells surrounds the enlarged bile ducts of livers in sheep and goats
Summary
Fasciola hepatica is known to establish chronic infections in its bovine host despite the development of a strong type-2/CD4+ Th2 response [1]. Further studies using Trichinella spiralis showed that regulation of the response against the muscle resident phase relied upon Foxp3+ CD4 T-cells and upon IL-10 from a distinct cellular source [5]; echoing those findings of Helmby and Grencis [6] who had demonstrated that IL-10 was effective at restraining the cellular response directed at larvae but not intestinal adults. These findings would suggest that Foxp expression alone is not responsible for the regulatory response to tissue helminths
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