CD4+CD25hiFOXP3+ Regulatory T Cells and Cytokine Responses in Human Schistosomiasis before and after Treatment with Praziquantel

Background: Chronic schistosomiasis is associated with T cell hypo-responsiveness and immunoregulatory mechanisms, including induction of regulatory T cells (Tregs). However, little is known about Treg functional capacity during human Schistosoma haematobium infection. Methodology: CD4+CD25hiFOXP3+ cells were characterized by flow cytometry and their function assessed by analysing total and Treg-depleted PBMC responses to schistosomal adult worm antigen (AWA), soluable egg antigen (SEA) and Bacillus Calmette-Guérin (BCG) in S. haematobium-infected Gabonese children before and 6 weeks after anthelmintic treatment. Cytokines responses (IFN-γ, IL-5, IL-10, IL-13, IL-17 and TNF) were integrated using Principal Component Analysis (PCA). Proliferation was measured by CFSE. Principal Findings: S. haematobium infection was associated with increased Treg frequencies, which decreased post-treatment. Cytokine responses clustered into two principal components reflecting regulatory and Th2-polarized (PC1) and pro-inflammatory and Th1-polarized (PC2) cytokine responses; both components increased post-treatment. Treg depletion resulted in increased PC1 and PC2 at both time-points. Proliferation on the other hand, showed no significant difference from pre- to post-treatment. Treg depletion resulted mostly in increased proliferative responses at the pre-treatment time-point only. Conclusions: Schistosoma-associated CD4+CD25hiFOXP3+Tregs exert a suppressive effect on both proliferation and cytokine production. Although Treg frequency decreases after praziquantel treatment, their suppressive capacity remains unaltered when considering cytokine production whereas their influence on proliferation weakens with treatment. Author Summary: Schistosomiasis, a parasitic worm infection, affects over 240 million people worldwide, especially children in sub-Saharan Africa. It is associated with immune hypo-responsiveness which results in an inability of the immune system to eliminate parasites. Animal models suggest that helminths induce regulatory T cells (Treg) which suppress effector cells and dampen anti-parasite activity as part of the parasites’ own strategy for survival in the human host. However, little is known about the functional capacity of Tregs during human Schistosoma haematobium infection and their interaction with adaptive responses. We designed a longitudinal study addressing the question of how anti-parasite treatment influences effector T cell activity and Treg function in peripheral blood of schoolchildren living in an S. haematobium endemic area in Lambaréné, Gabon. Our findings show that schistosome infection is associated with increased Treg frequency and that Tregs exert a suppressive effect on immune cell function in terms of both proliferation and cytokine production. Although Treg frequency decreases after anti-schistosome treatment, their suppressive capacity remains unaltered for cytokine production but their influence on proliferation weakens with treatment. By understanding how immune system is prevented from killing parasites, we hope to offer a novel route for intervention to achieve an immunological cure.