The Common γ Chain Cytokines Interleukin (IL)–2 and IL-7 Indirectly Modulate Blood Fluke Development via Effects on CD4+ T Cells

The blood fluke Schistosoma mansoni is a causative agent of schistosomiasis and a major global health problem. After penetrating the skin of the host, schistosomula migrate via the bloodstream to the portal circulation, arriving during the second week of infection [1]. On reaching the liver, migration ceases, and rapid growth and development ensues [2], culminating in the sexual maturation of the parasites, pairing, and the onset of oviposition at ~5 weeks after infection. Eggs are deposited in and transit across the wall of the intestine, emerging into the lumen and passing from the body in feces. Deposition of eggs in host tissues and the resulting inflammatory and immune responses are the primary cause of the pathological and clinical manifestations associated with schistosome infection. Deposition of schistosome eggs in the bowel wall and other tissues induces formation of granulomas around the eggs, a process that is mediated by CD4+ Th2 responses to egg antigens [3]. Formation of granulomas around schistosome eggs appears to facilitate the transit of eggs across the intestinal wall and their egress from the body [4]. Interestingly, CD4+ T cells also facilitate S. mansoni development during the prepatent period, because parasite development is severely impaired in immunodeficient mice and normal development is restored by adoptive transfer of CD4+ T cells into immunodeficient mice [5]. Taken together, these findings may explain why patients with schistosomiasis who are coinfected with HIV excrete fewer eggs in their feces than patients who are HIV negative [6]. Observations from patients with schistosome-HIV coinfection highlight a general recurring theme in helminth-HIV coinfections—that, in contrast to bacteria, fungi, and protozoa, immunosuppression by HIV does not lead to fulminant helminth infections [7]. Rather, HIV coinfection either has little effect on helminth infections, as is the case with most intestinal helminths [7], or may create conditions that are unfavorable to helminth development in the host, as is the case for Strongyloides stercoralis infection [8]. The latter finding correlates well with the notable lack of association between HIV infection and disseminated strongyloidiasis [7]. Attenuated schistosome development was also reported in IL-7–deficient (IL-7−/−) mice [9], suggesting that this host factor may play a direct role in promoting parasite development. Because IL-7 is not expressed by T lymphocytes but is produced by endothelial and epithelial cells such as thymic stromal cells, it is possible that IL-7 represents a distinct mechanism by which host factors modulate schistosome development. However, IL-7 is critical for the thymic development of T lymphocytes and their subsequent survival in the periphery, as demonstrated by the severely lymphopenic phenotype of IL-7−/− [10] and IL-7 receptor (IL-7R)−/− [11] mice. We, therefore, hypothesized that the defective schistosome development reported in IL-7−/− mice was the indirect result of impaired T cell development and T lymphopenia in the absence of IL-7 signaling rather than the result of a direct effect that IL-7 has on schistosomes. To test this hypothesis, we examined schistosome infections in mice that lack components of the IL-7R complex (IL-7Rα and common γ [γc] chains) because IL-7 signaling is abrogated in these mice [11, 12] but IL-7 synthesis is intact, as demonstrated by their ability to sustain homeostatic proliferation of adoptively transferred IL-7R–expressing T cells [13]. Our data support the conclusion that the effects that IL-7 has on schistosome development are indeed mediated indirectly via the effects that IL-7 has on T cell homeostasis. Furthermore, our analyses identify an indirect role that another γc cytokine, IL-2, plays in schistosome development. Thus, although expression of Th1 or Th2 phenotypes and their associated effector cytokines by CD4+ T cells does not play a role in schistosome development [5, 14], autocrine production of the T cell growth factor IL-2 by CD4+ T cells is essential to the mechanism by which these cells modulate blood fluke development.