Abstract
We had formerly demonstrated that subjects chronically infected with Trypanosoma cruzi show impaired T cell responses closely linked with a process of T cell exhaustion. Recently, the expression of several inhibitory receptors has been associated with T cell dysfunction and exhaustion. In this study, we have examined the expression of the cytotoxic T lymphocyte antigen 4 (CTLA-4) and the leukocyte immunoglobulin like receptor 1 (LIR-1) by peripheral T. cruzi antigen-responsive IFN-gamma (IFN-γ)-producing and total T cells from chronically T. cruzi-infected subjects with different clinical forms of the disease. CTAL-4 expression was also evaluated in heart tissue sections from subjects with severe myocarditis. The majority of IFN-γ-producing CD4+ T cells responsive to a parasite lysate preparation were found to express CTLA-4 but considerably lower frequencies express LIR-1, irrespective of the clinical status of the donor. Conversely, few IFN-γ-producing T cells responsive to tetanus and diphtheria toxoids expressed CTLA-4 and LIR-1. Polyclonal stimulation with anti-CD3 antibodies induced higher frequencies of CD4+CTAL-4+ T cells in patients with severe heart disease than in asymptomatic subjects. Ligation of CTLA-4 and LIR-1 with their agonistic antibodies, in vitro, reduces IFN-γ production. Conversely, CTLA-4 blockade did not improved IFN-γ production in response to T. cruzi antigens. Subjects with chronic T. cruzi infection had increased numbers of CD4+LIR-1+ among total peripheral blood mononuclear cells, relative to uninfected individuals and these numbers decreased after treatment with benznidazole. CTLA-4 was also expressed by CD3+ T lymphocytes infiltrating heart tissues from chronically infected subjects with severe myocarditis. These findings support the conclusion that persistent infection with T. cruzi leads to the upregulation of inhibitory receptors which could alter parasite specific T cell responses in the chronic phase of Chagas disease.
Highlights
Chagas disease, caused by Trypanosoma cruzi infection, is the most frequent cause of infectious cardiomyopathy in the world, with approximately 4 million individuals presenting heart disease [1]
We have previously shown that increased severity of chronic Chagas disease in humans was associated with impaired T cell responses specific for T. cruzi and with signs of exhaustion in the overall T cell compartment [29,30]
To explore the possibility that negative regulatory pathways are involved in the poor T. cruzispecific T cell responses in long-term infected subjects, we evaluated intracellular cytotoxic T lymphocyte antigen 4 (CTLA-4) expression – that represent most of the total CTLA-4 molecules synthesized [39] – and like receptor 1 (LIR-1) by CD4+ T cells subjected to T. cruzi antigens stimuli in chronically infected subjects without cardiac symptoms (Group G0) and in a group of patients with severe chagasic cardiomyopathy (Group G3)
Summary
Chagas disease, caused by Trypanosoma cruzi infection, is the most frequent cause of infectious cardiomyopathy in the world, with approximately 4 million individuals presenting heart disease [1]. CD4+ and CD8+ T responses are involved in the control of the acute Trypanosoma cruzi infection and keep the parasite burden under control during the chronic phase of the infection. T cells initially acquire effector functions but gradually become less functional as the infection progresses. This loss of function, known as exhaustion, is hierarchical, with the proliferative potential and production of interleukin 2 (IL-2) lost early, followed by the ability to make tumor necrosis factor alpha, while IFNgamma (IFN-c) production is most resistant to functional exhaustion [5,10]
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