Presence of antigen-experienced T cells with low grade of differentiation and proliferative potential in chronic Chagas disease myocarditis.

Rafael J. Argüello,Rubén Laguens,Fernando Garelli,Roberto R. Favaloro,Susana A. Laucella,Rodolfo Viotti,Patricia Cabeza-Meckert,Liliana E. Favaloro,Carlos Vigliano,Mauricio Martins Rodrigues

doi:10.1371/journal.pntd.0002989

Abstract

BackgroundThe main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20–30% of infected individuals but not until 10–20 years after the initial infection. We have previously shown that circulating interferon-γ-secreting T cells responsive to Trypanosoma cruzi antigens in chronic Chagas disease patients display a low grade of differentiation and the frequency of these T lymphocytes decreases along with the severity of heart disease. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis.Methodology/Principal FindingsThe expression of different markers for T and B cells as well as for macrophages was evaluated by immunohistochemistry and immunofluorescence techniques in cardiac explants from patients with advanced chronic Chagas disease submitted to heart transplantation. Most infiltrating cells displayed markers of antigen-experienced T cells (CD3+, CD4+, CD8+, CD45RO+) with a low grade of differentiation (CD27+, CD57−, CD45RA−, PD-1−). A skewed T helper1/T cytotoxic 1 profile was supported by the expression of T-bet; whereas FOXP3+ cells were scarce and located only in areas of severe myocarditis. In addition, a significant proliferative capacity of CD3+ T cells, assessed by Ki67 staining, was found.Conclusions/SignificanceThe quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection.

Highlights

The main consequence of chronic Trypanosoma cruzi (T. cruzi) infection is the development of myocarditis in approximately 20– 30% of infected individuals but not until 10–20 years after the initial infection [1]
Conclusions/Significance: The quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection
A Th1 cytokine pattern predominated in the cardiac inflammatory cell infiltrate of Chagas disease patients with heart failure [9].Whereas some authors have shown increased peripheral levels of IFN-c in patients with severe heart disease [10,11,12], other studies have demonstrated an inverse association between disease severity and IFN-c production [8,13,14].We have previously shown that most IFN-c-secreting T cells in response to T. cruzi display a low grade of differentiation but high expression of the inhibitory receptor cytotoxic lymphocyte antigen 4 (CTLA-4) in the circulation of subjects with chronic T. cruzi infection [8,15,16]

Summary

Introduction

The main consequence of chronic Trypanosoma cruzi (T. cruzi) infection is the development of myocarditis in approximately 20– 30% of infected individuals but not until 10–20 years after the initial infection [1]. A Th1 cytokine pattern predominated in the cardiac inflammatory cell infiltrate of Chagas disease patients with heart failure [9].Whereas some authors have shown increased peripheral levels of IFN-c in patients with severe heart disease [10,11,12], other studies have demonstrated an inverse association between disease severity and IFN-c production [8,13,14].We have previously shown that most IFN-c-secreting T cells in response to T. cruzi display a low grade of differentiation but high expression of the inhibitory receptor CTLA-4 in the circulation of subjects with chronic T. cruzi infection [8,15,16]. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis

Methods

Results

Discussion

Conclusion