Innate and adaptive immune mechanisms that induce pathogenic Th17 responses in murine schistosomiasis

Infection with Schistosoma mansoni results in a CD4 T cell-mediated granulomatous inflammatory reaction against tissue-trapped parasite eggs, that varies greatly in magnitude both in humans and among mouse strains. Naturally occurring severe disease observed in CBA/J (CBA) mice, or induced by concomitant immunization with schistosome egg antigens (SEA) emulsified in complete Freund's adjuvant (SEA/CFA) in typically low pathology C57BL/6 (BL/6) mice, is characterized by marked inflammation associated with robust production of IFN-gamma and IL-17. In contrast, milder immunopathology, demonstrated in BL/6 mice, correlates with a largely anti-inflammatory immune response. The precise immune mechanisms governing the development of severe or mild forms of schistosomiasis have yet to be fully elucidated. Observations from SEA/CFA-immunized schistosome-infected mice lacking the IL-27 receptor chain WSX-1 revealed that IL-27 was vital for optimal IFN-beta production by SEA-stimulated cells, but dispensable for IL-17 secretion and the development of severe immunopathology. In subsequent studies, using an in vitro DC-CD4 T cell co-culture system, we demonstrated that live schistosome eggs induced the production of the Th2-associated cytokine IL-5 in BL/6 co-cultures. In contrast, egg-stimulated CBA co-cultures secreted enhanced levels of the severe pathology-associated cytokine IL-17 and the differentiation of Th17 cells was demonstrated to be critically dependent upon IL-23 and IL-1beta, but not IL-6 or IL-21. Furthermore, in co-cultures using cells from novel IL-12p40-/- and Sm-p40 egg antigen-specific TCR transgenic mice, both on the high pathology-prone CBA background, IL-23 and IL-1beta were shown to be essential for the differentiation of egg antigen-specific Th17 cells. We also conclude that soluble egg-derived molecule(s) mediate the secretion of IL-17 in CBA DC-CD4 T cell co-cultures. Microarray analysis of unstimulated DCs revealed markedly enhanced expression of C-type lectin receptors in CBA DCs, suggesting a glycan-sensing gene profile, whereas BL/6 DCs demonstrated a broader, anti-inflammatory-skewed phenotype. Additionally, egg-stimulated CBA DCs exhibited a proinflammatory gene profile punctuated by augmented IL-1beta expression, while the enhancement of general anti-inflammatory genes was observed in BL/6 DCs. These findings suggest that DCs derived from genetically susceptible hosts differentially recognize schistosome egg antigens that precipitate a proinflammatory cascade driven by IL-23 and IL-1beta, ultimately resulting in the differentiation of pathogenic Th17 cells and exacerbation of disease.