Abstract
BackgroundThe severity of cardiac disease in chronic Chagas disease patients is associated with different features of T-cell exhaustion. Here, we assessed whether the ability of T cells to secrete IFN-γ in response to T. cruzi was linked to disruption in immune homeostasis and inflammation in patients with chronic Chagas disease.Methodology/Principal findingsPBMCs from chronic Chagas disease patients and uninfected controls were examined for frequencies of T. cruzi-responsive IFN-γ-producing cells by ELISPOT and cellular expression and function of IL-7R using flow cytometry. Serum levels of IL-7, IL-21, IL-27, soluble IL-7R, and inflammatory cytokines were also evaluated by ELISA or CBA techniques. Patients possessing T. cruzi-specific IFN-γ-producing cells (i.e. IFN-γ producers) had higher levels of memory T cells capable of modulating the alpha chain of IL-7R and an efficient response to IL-7 compared to that in patients lacking (i.e. IFN-γ nonproducers) parasite-specific T-cell responses. IFN-γ producers also showed low levels of soluble IL-7R, high basal expression of Bcl-2 in T cells and low basal frequencies of activated CD25+ T cells. Modulation of IL-7R was inversely associated with serum IL-6 levels and positively associated with serum IL-8 levels. Circulating IL-21 and IL-27 levels were not associated with the frequency of IFN-γ producing cells but were reduced in less severe clinical forms of the disease. In vitro stimulation of PBMCs with IL-7 or IL-27 enhanced IFN-γ production in IFN-γ producers but not in IFN-γ nonproducers.Conclusions/SignificanceAlterations of the IL-7/IL-7R axis and in the levels of inflammatory cytokines were linked to impaired T. cruzi-specific IFN-γ production. These alterations might be responsible of the process of immune exhaustion observed in chronic Chagas disease.
Highlights
Chagas disease is a major health problem in Latin America and an increasing threat in other countries that are non-endemic for Trypanosoma cruzi infection [1,2,3,4]
Mechanisms of acquired immune response against Trypanosoma cruzi antigens include both humoral and cellular components that might be critical in a chronic infection
We investigated whether the ability of T cells to secrete IFN-γ in response to T. cruzi was linked to the expression and function of the IL-7 receptor and the cytokines involved in regulating this axis in patients with different clinical forms of chronic Chagas disease
Summary
Chagas disease is a major health problem in Latin America and an increasing threat in other countries that are non-endemic for Trypanosoma cruzi infection [1,2,3,4]. Other feature of immune exhaustion of T cells in chronic Chagas disease is the expression of cytotoxic T lymphocyte antigen 4 by IFN-γ-producing CD4+ T cells in response to T. cruzi [13] and in the total T-cell compartment [13,14,15]. CTLA-4 expression was observed in CD3+ T lymphocytes infiltrating the heart tissues of chronically infected subjects with severe myocarditis [13]. These findings suggest that parasite persistence induces overexpression of inhibitory receptors that might regulate deleterious consequences of a sustained immune response and dampens the parasite-specific T-cell responses necessary for parasite control. We assessed whether the ability of T cells to secrete IFN-γ in response to T. cruzi was linked to disruption in immune homeostasis and inflammation in patients with chronic Chagas disease
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