Abstract
Dendritic cells (DCs) are the key initiators of T-helper (Th) 2 immune responses against the parasitic helminth Schistosoma mansoni. Although the liver is one of the main sites of antigen deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni antigens in vivo, or how the liver microenvironment might influence DC function during establishment of the Th2 response. In this study, we show that hepatic DC subsets undergo distinct activation processes in vivo following murine infection with S. mansoni. Conventional DCs (cDCs) from schistosome-infected mice upregulated expression of the costimulatory molecule CD40 and were capable of priming naive CD4+ T cells, whereas plasmacytoid DCs (pDCs) upregulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naive or effector/memory CD4+ T cells. Importantly, in vivo depletion of pDCs revealed that this subset was dispensable for either maintenance or regulation of the hepatic Th2 effector response during acute S. mansoni infection. Our data provides strong evidence that S. mansoni infection favors the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing antigen exposure.
Highlights
S. mansoni infection is associated with increased numbers of Dendritic cells (DCs) in the liver effector site and dramatic changes in gene expression The liver is one of the principal effector sites during S. mansoni infection, with parasite eggs that are carried there by the blood flow becoming trapped in the sinusoids and forming the foci of immunemediated granulomas.[4]
There were no significant differences between the proportion of Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) in the liver preparations, there was a significant increase in the total number of both populations (Figure 1d), indicating that DCs are recruited to, or differentiate within, this major effector site during acute S. mansoni infection
We have examined the direct impact of acute S. mansoni infection on the two major functional classes of CD11c+ DCs found in the liver effector site in vivo
Summary
S. mansoni eggs are metabolically active and highly immunogenic and, while many successfully exit the host by traversing the lumen of the gastrointestinal tract, some eggs are carried by the blood flow into the liver, where they become trapped in the sinusoids and induce inflammation and granuloma formation.[4,8] The liver is one of the main sites of Ag exposure during S. mansoni infection and the Th2-dominated granuloma response, which serves to protect hepatocytes from toxins released by tissue-trapped eggs, is thought to be essential for host survival.[9,10,11] Development of the egg-specific Th2 response begins 4–6 weeks after infection, with the peak of the ‘acute’ response occurring around week 8, before a combination of regulatory mechanisms and T-cell exhaustion combine to dampen down the response during the ‘chronic’ stage from approximately week 12 onwards.[4,7,12,13] Th2 responses are protective during the initial stages of acute schistosomiasis, prolonged production of interleukin (IL)-4/IL-13 contributes to liver inflammation, fibrosis and immunopathology during chronic infection, and host survival is dependent on mounting a balanced T-helper response.[4,14]
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