Deficient Regulatory T Cell Activity and Low Frequency of IL-17-Producing T Cells Correlate with the Extent of Cardiomyopathy in Human Chagas' Disease

Abstract

Background

Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1–Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease.

Methodology/Principal Findings

First, we observed CD4 ⁺IL-17 ⁺ T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4 ⁺IL-17 ⁺ cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4 ⁺CD25 ⁺ regulatory T cells. However, CD4 ⁺CD25 ⁺ T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = −0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500).

Conclusion/Significance

These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.

Author Summary

Dilated cardiomyopathy is one of the clinical forms of Chagas' disease (CD) after the infection caused by the parasite Trypanosoma cruzi. Even though strategies adopted in most Latin-American countries in the last decades towards vector control have been effective in reducing the incidence of CD, active transmission is maintained in some regions, and secondary prevention approaches are still required for the infected patients, mostly because the specific anti-parasitic medications are toxic and perhaps of limited efficacy in chronically infected individuals. Moreover, there are no markers to predict the risk of developing dilated cardiomyopathy in asymptomatic, chronically infected patients, although the failure in the mechanisms that control the immune response can be involved in the development of Chagas' heart disease. In this study we show that preserved activity of regulatory T cells and the production of the cytokine IL-17 are connected with a more benign evolution of the disease, which brings a new understanding on the mechanisms associated with progression of CD.