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

Yvonne Schmiedel,Saadou Issifou,Jacqueline J Janse,Maria Yazdanbakhsh,Ayôla A Adegnika,Ghyslain Mombo-Ngoma,Brechje De Gier,Peter G Kremsner,Hermelijn H Smits,Lucja A Labuda,Jeffrey Michael Bethony

doi:10.1371/journal.pntd.0003995

Abstract

BackgroundChronic 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.MethodologyCD4+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.

Highlights

The immune system has evolved several regulatory mechanisms to maintain immune homeostasis, prevent autoimmunity and restrain inflammation [1,2,3]
To investigate whether S. haematobium infection affects the frequency of peripheral blood Tregs we compared circulating CD4+CD25hiFOXP3+ Tregs from infected and uninfected children by flow cytometry
We found that frequencies of FOXP3+ Tregs were significantly higher in infected children compared to uninfected children (Fig 1B)

Summary

Introduction

The immune system has evolved several regulatory mechanisms to maintain immune homeostasis, prevent autoimmunity and restrain inflammation [1,2,3]. When chronic in nature it has been shown to be associated with general T cell hypo-responsiveness—evident from down-modulated antigen-specific Th1 and Th2 cell responses [6,7]]. This might result from mechanisms involving peripheral anergy and suppression triggered by regulatory cells, such as Tregs [8]. In experimental murine models, it was observed that the presence of regulatory T cells was associated with suppressed development of pathology [9], and down-modulated Th1 and Th2 responses [10,11], promoting parasite survival within the host [12,13]. Little is known about Treg functional capacity during human Schistosoma haematobium infection.

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