A central role for hepatic conventional dendritic cells in supporting Th2 responses during helminth infection

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 Ag deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni Ags 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 up-regulated expression of the costimulatory molecule CD40 and were capable of priming naïve CD4+ T cells, whereas plasmacytoid DCs (pDCs) up-regulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naïve 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 favours the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing Ag exposure.

Type I interferon is required for T helper (Th) 2 induction by dendritic cells

“…Notably, in most cases, the degree to which activation molecules were upregulated was less striking with SEA than St ( Fig EV1). This muted cDC surface activation following exposure to SEA is in keeping with previous reports of GMDCs or human PBMC DCs exposed to SEA in vitro, or splenic and hepatic DCs from S. mansoni-infected mice, and may reflect an alternative, and more restricted, DC activation phenotype that is common to Th2 settings (MacDonald et al, 2001;de Jong et al, 2002;Straw et al, 2003;MacDonald & Maizels, 2008;Lundie et al, 2016).…”

Immunity to gastrointestinal nematode infections

“…Interestingly, some studies suggest that ILC, 129-131 basophils, [132][133][134] and eosinophils 135,136 can express major histocompatibility complex class II and directly prime Th2 responses, notably upon N. brasiliensis 131 and T. muris 132 infections, with each cell type having been shown to migrate to the mesenteric lymph nodes during infection. 85,87,137,138 However, given that protective immunity is abolished in mice where all 139,140 or specific subsets 104-106,108,109 of dendritic cells have been depleted, it is perhaps more likely that these other innate cells contribute to local tissue immunity by promoting dendritic cell activation, or by further enhancing the cytokine response of mature T cells that have migrated to the infected tissue. 53 Moreover, dendritic cells are responsive not only to cytokines produced by other innate cells, but also to epithelium-derived cytokines, including TSLP, 54,[141][142][143] IL-25, 144 and IL-33, 52,145 thus potentially bypassing ILC2 and granulocytes entirely.…”

T Lymphocyte-Mediated Liver Immunopathology of Schistosomiasis

“…Ma et al uncovered a novel subset of CD11c + CD49b + FcεRI + DCs that can produce IL-4 and subsequently promote Th2 differentiation in an IL-4-dependent manner (146). However, contradictory findings revealed that conventional DCs are critical subsets for Th2 effector cell development during acute S. mansoni infection (147). In fact, more researchers support the notion that DCs do not need to produce IL-4 to promote Th2 development (148)(149)(150) because IL-4-deficient DCs still show the ability to induce excellent Th2 responses (148).…”