The common gamma chain cytokines interleukin (IL)-2 and IL-7 indirectly modulate blood fluke development via effects on CD4+ T cells

Abstract

The human pathogen Schistosoma mansoni exhibits a highly evolved and intricate relationship with its host, evading immune destruction while co-opting CD4(+) T cell-driven mechanisms to facilitate parasite development and egg excretion. Because the common gamma ( gamma (c)) chain cytokine interleukin (IL)-7 is also implicated in modulating schistosome development, we investigated whether this effect is mediated indirectly through the essential role that IL-7 plays in CD4(+) T cell growth and survival. We demonstrate that attenuated schistosome development in the absence of IL-7 results from dysregulated T cell homeostasis and not from disruption of direct interactions between schistosomes and IL-7. We also identify an indirect role that another gamma (c) chain cytokine plays in schistosome development, demonstrating that IL-2 expression by CD4(+) T cells is essential for normal parasite development. Thus, cytokines critical for CD4(+) T cell survival and function can mediate indirect but potent effects on developing schistosomes and underscore the importance of CD4(+) T cells in facilitating schistosome development.

Figure 1

Schistosoma mansoni development in interleukin-7 receptor α–deficient (IL-7Rα^−/−) mice. IL-7Rα^−/− and wild-type mice were infected percutaneously with S. mansoni cercariae, and parasite development and egg production were assessed at 6 weeks after infection. A, S. mansoni worms isolated from wild-type mice. B, S. mansoni worms isolated from IL-7Rα^−/− mice. C, Length of male S. mansoni worms isolated from wild-type and IL-7Rα^−/− mice. D, Percentage of female worms participating in pairs in wild-type and IL-7Rα^−/− mice. E, No. of eggs deposited per pair of worms in the livers of wild-type and IL-7Rα^−/− mice. The scale bars in panels A and B represent a length of 1 mm. P values were calculated using the Mann-Whitney U test.

Figure 2

Schistosoma mansoni development in common γ chain–deficient (γ_c^−/−) mice. γ_c^−/− and wild-type mice were infected percutaneously with S. mansoni cercariae, and parasite development and egg production were assessed at 6 weeks after infection. A, S. mansoni worms isolated from wild-type mice. B, S. mansoni worms isolated from γ_c^−/− mice. C, Length of male S. mansoni worms isolated from wild-type and γ_c^−/− mice. D, Percentage of female worms participating in pairs in wild-type and γ_c^−/− mice. E, No. of eggs deposited per pair of worms in the livers of wild-type and γ_c^−/− mice. The scale bars in panels A and B represent a length of 1 mm. P values were calculated using the Mann-Whitney U test.

Figure 3

Schistosoma mansoni development in interleukin (IL)–2–deficient (IL-2^−/−) mice. IL-2^−/− and wild-type mice were infected percutaneously with S. mansoni cercariae, and parasite development and egg production were assessed at 6 weeks after infection. A, Length of male S. mansoni worms isolated from wild-type and IL-2^−/− mice. B, Percentage of female worms participating in pairs in wild-type and IL-2^−/− mice. C, No. of eggs deposited per pair of worms in the livers of wild-type and IL-2^−/− mice. P values were calculated using the Mann-Whitney U test.

Figure 4

Schistosoma mansoni development in interleukin-2 receptor α–deficient (IL-2Rα^−/−) mice. IL-2Rα^−/− and wild-type mice were infected percutaneously with S. mansoni cercariae, and parasite development and egg production were assessed at 6 weeks after infection. A, Length of male S. mansoni worms isolated from wild-type and IL-2Rα^−/− mice. B, Percentage of female worms participating in pairs in wild-type and IL-2Rα^−/− mice. C, No. of eggs deposited per pair of worms in the livers of wild-type and IL-2Rα^−/− mice. P values were calculated using the Mann-Whitney U test.

Figure 5

Schistosoma mansoni development in recombination activating gene (RAG)–1–deficient (RAG-1^−/−) mice reconstituted with CD4⁺CD25⁻ and CD4⁺CD25⁺ T cells from wild-type donors. One day before infection, RAG-1^−/− recipients were reconstituted with 4 × 10⁶ CD4⁺CD25⁻ or CD4⁺CD25⁺ T cells from wild-type donors, and S. mansoni worm development and egg production were assessed at 6 weeks after infection. A, Length of male S. mansoni worms isolated from RAG-1^−/− recipients reconstituted with PBS alone, CD4⁺CD25⁻ T cells, or CD4⁺CD25⁺ T cells; overall P < .0001, Kruskal-Wallis test. B, Percentage of female worms participating in pairs in RAG-1^−/− recipients reconstituted with PBS alone, CD4⁺CD25⁻ T cells, or CD4⁺CD25⁺ T cells; overall P = .0306, Kruskal-Wallis test. C, No. of eggs deposited per pair of worms in the livers of RAG-1^−/− recipients reconstituted with PBS alone, CD4⁺CD25⁻ T cells, or CD4⁺CD25⁺ T cells; overall P = .0266, Kruskal-Wallis test. In panels A, B, and C, P values for each experimental group pair were calculated using Dunn’s multiple comparison test.

Figure 6

Schistosoma mansoni development in recombination activating gene (RAG)–1–deficient (RAG-1^−/−) mice reconstituted with interleukin (IL)–2^−/− or wild-type CD4⁺ T cells. One day before infection, RAG-1^−/− recipients were reconstituted with 4 × 10⁶ CD4⁺ T cells from wild-type (IL-2^+/+) or IL-2^−/− donors, and S. mansoni worm development and egg production were assessed at 6 weeks after infection. A, Length of male S. mansoni worms isolated from RAG-1^−/− recipients reconstituted with PBS alone, IL-2^+/+ CD4⁺ T cells, or IL-2^−/− CD4⁺ T cells); overall P <.0001, Kruskal-Wallis test. B, Percentage of female worms participating in pairs in RAG-1^−/− recipients reconstituted with PBS alone, IL-2^+/+ CD4⁺ T cells, or IL-2^−/− CD4⁺ T cells; overall P = .5833, Kruskal-Wallis test. C, No. of eggs deposited per pair of worms in the livers of RAG-1^−/− recipients reconstituted with PBS alone, IL-2^+/+ CD4⁺ T cells, or IL-2^−/− CD4⁺ T cells; overall P = .0474, Kruskal-Wallis test. In panels A, B, and C, P values for each experimental group pair were calculated using Dunn’s multiple comparison test.