Induction of Type 2 Responses by Schistosome Worms during Prepatent Infection

Blood flukes of the genus Schistosoma infect >1200 million people globally, causing significant morbidity and mortality. As is the case with other helminths, schistosome infection ultimately results in establishment of a CD4+ T helper type 2 (Th2) response, both in human patients [1] and in laboratory animal models [2]. This response is characterized by production of immunoglobulin E (IgE) and eosinophilia, driven by the type 2 cytokines interleukin (IL)–4 [3] and IL-5 [4], respectively. Schistosome eggs are an important stimulus for type 2 responses during schistosome infection, because the onset of egg laying at 5–6 weeks after infection is accompanied by a robust Th2 response to egg antigens [5] that is critical for formation of granulomas around the eggs [6]. Indeed, schistosome eggs and egg antigens are potent, autonomous inducers of Th2 responses, even in the absence of schistosome worms, because Th2 responses are readily induced when intact eggs [7, 8] or egg antigen–pulsed dendritic cells [9] are introduced into naive animals. Ironically, egg-induced Th2 responses are an immunologic double-edged sword, participating in protection of host tissues from egg-induced injury [10] and in the development of the egg-induced pathology and fibrosis associated with chronic schistosome infection [11]. In contrast to schistosome eggs, the contribution of schistosome worms to the induction of adaptive responses and the subsequent development of pathology has received less consideration. Immune responses induced by schistosome worms are of biomedical significance for 3 reasons. First, acquired immunity to schistosome worms that results in reduced parasite burdens can be demonstrated in naturally exposed human subjects [12] and laboratory animal models of vaccine-induced immunity [13]. Although the mechanisms by which protection is mediated under these different circumstances are debated [12, 14], these observations suggest that induction of protective responses to schistosome worms, perhaps through vaccination, may be a feasible approach to controlling schistosomiasis [12]. Second, although schistosome eggs can induce Th2 responses independently of schistosome worms [7], naturally infected hosts are exposed to schistosome worms first, well before eggs are produced, providing ample opportunity for establishment and modulation of responses to cross-reactive antigenic epitopes that are common to both worms and eggs [15–19]. Indeed, there is evidence that worm-induced responses during prepatent infection do influence the subsequent response to eggs and can significantly alter egg-induced immunopathology [18, 20, 21]. Finally, we and others have provided evidence that the activities of CD4+ T cells during prepatent infection promote the development and reproductive fitness of schistosome worms [22, 23]. Together, these observations suggest that CD4+ T cell responses to schistosome worms have both positive and negative effects on the establishment of schistosome infection and the subsequent course of disease. This intimate relationship is presumably a reflection of extensive host-parasite coevolution, resulting in a relationship where schistosomes induce CD4+ T cell responses that facilitate establishment of infection while simultaneously avoiding excessive pathological damage to the host. An understanding of the CD4+ T cell responses induced by schistosome worms is therefore a prerequisite to identifying immune responses that can be modified to the benefit of the host and the detriment of the parasite. In contrast to eggs, exposure to schistosome worms during the prepatent phase of infection was shown to induce modest production of interferon (IFN)–γ by CD4+ T cells [5, 8], leading to the conclusion that, unlike other helminths, schistosome worms induce an initial T helper type 1 (Th1) response that is subsequently down-modulated and replaced by an egg-induced T helper type 2 (Th2) response when egg deposition begins [24, 25]. However, there are reasons to suspect that responses to schistosome worms during prepatent infection are more complex. First, there is evidence of both circulating eosinophilia [26] and increased eosinopoiesis [27] during the first weeks of infection, responses typically mediated by the Th2 cytokine IL-5 [4]. Second, analyses of cutaneous responses to cercariae suggest that invading schistosome larvae stimulate a mixed T helper response in the skin, with evidence of both Th1 and Th2 polarization at the site of infection [28, 29]. In light of these findings, we tested the hypothesis that schistosome worms induce systemic type 2 responses before the onset of egg-laying, resulting in the development of worm antigen-specific IL-4–producing CD4+ T cells and IgE. Our data show that both these hallmarks of Th2 responses are readily detectable during prepatent infection, to the extent that basophils become sensitized to produce IL-4 in response to worm antigens well in advance of egg deposition. These data provide fresh insights into the phenotype of CD4+ T cell responses to schistosome worms during natural infection and have implications for understanding the role of worm-induced responses in the subsequent pathogenesis of egg-induced disease.