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. 2015 Aug 20;9(8):e0003995.
doi: 10.1371/journal.pntd.0003995. eCollection 2015 Aug.

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

Affiliations

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

Yvonne Schmiedel et al. PLoS Negl Trop Dis. .

Abstract

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Increased frequency of CD4+CD25hiFOXP3+ Tregs during S. haematobium infection.
Gating strategy for identification of CD4+CD25hiFOXP3+ Tregs (A). CD4 T cells were identified and Boolean gating combinations were used to determine proportions of CD4+CD25hiFOXP3+ Tregs (B). Differences between groups were tested with a Mann-Whitney U test and within groups with a Wilcoxon matched pairs test. Horizontal bars represent median. * p< 0.05, ** p< 0.01.
Fig 2
Fig 2. Proliferative responses to schistosome specific and non-specific antigens.
CFSE-labelled total PBMC from S. haematobium infected children pre- and 6 weeks post-treatment were left unstimulated (medium), or stimulated with S. haematobium adult worm antigen (AWA) and soluble egg antigen (SEA) and Bacillus Calmette–Guérin (BCG). After 4 days of culture cells were fixed, cryopreserved and after thawing CFSE division was analyzed for CD4+CD25hi T cells by flow cytometry. Results are shown as median with IQR. Differences between pre-treatment and 6 weeks post-treatment responses were tested with a Wilcoxon matched pairs test.
Fig 3
Fig 3. Principal component analysis (PCA) of cytokine responses to schistosome specific and non-specific antigens.
Two distinct principal components were identified: principal component 1 (PC1) which reflects regulatory and Th2-polarized cytokine responses due to its positive loading with IL-5, IL-10 and IL-13 responses; and principal component 2 (PC2) which reflects pro-inflammatory and Th1-polarized cytokine responses due to its positive loading with IFN-γ, IL-17 and TNF.
Fig 4
Fig 4. Effect of Treg depletion on proliferative responses to schistosome specific and non-specific antigens.
CFSE-labeled total or CD4+CD25hiFOXP3+ depleted PBMC from S. haematobium infected children pre- and 6 weeks post-treatment were left unstimulated (medium), or stimulated with S. haematobium adult worm antigen (AWA) and soluble egg antigen (SEA) and Bacillus Calmette–Guérin (BCG). After 4 days of culture cells were fixed, cryopreserved and after thawing CFSE division was analyzed for CD4+CD25hi T cells by flow cytometry. Results are shown as median with IQR (A). Differences between total and depleted PBMC were tested with a Wilcoxon matched pairs test. * p< 0.05, ** p< 0.01. Representative plot of CFSE staining illustrating proliferation of total or Treg depleted PBMC (B).

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