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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anthelmintics / therapeutic use*
  • CD4 Antigens / immunology
  • Child
  • Cohort Studies
  • Cytokines / metabolism*
  • Female
  • Forkhead Transcription Factors / immunology
  • Gene Expression Regulation / physiology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Longitudinal Studies
  • Male
  • Peptide Fragments / immunology
  • Praziquantel / therapeutic use*
  • Schistosomiasis haematobia / drug therapy*
  • Schistosomiasis haematobia / immunology
  • Schistosomiasis haematobia / metabolism
  • T-Lymphocytes, Regulatory / classification*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Anthelmintics
  • CD4 Antigens
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2 Receptor alpha Subunit
  • Peptide Fragments
  • CD4 (76-94)
  • Praziquantel

Grants and funding

This work was supported by the EU-funded project T Cell Regulation and the Control of Helminth Infections “TRANCHI” (INCO-CT-2006-032436) and the EU-funded project Innate Immune Responses and Immunoregulation in Schistosomiasis: Novel mechanisms in the control of infection and disease “SCHISTOINIR” (INCO-CT-2006-032405). We acknowledge support by Deutsche Forschungsgemeinschft and Open Access Publishing fund of University Tübingen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.