Antiparasitic Treatment Induces an Improved CD8+ T Cell Response in Chronic Chagasic Patients

Abstract

Chagas disease is a chronic infection caused by an intracellular protozoan parasite. Chronic chagasic patients (CCPs) have dysfunctional CD8 T cells that are characterized by impaired cytokine production, high coexpression of inhibitory receptors, and advanced cellular differentiation. Most patients diagnosed in the chronic phase of Chagas disease already exhibit heart involvement, and there is no vaccination that protects against the disease. Antiparasitic treatment is controversial as to its indication for this stage of the disease. There is a lack of biological markers to evaluate the effectiveness of antiparasitic treatment, and little is known about the effect of the treatment on CD8 T cells. Thus, the aim of the current study was to analyze the early effects of antiparasitic treatment on CD8 T cells from CCPs with asymptomatic clinical forms of disease. To evaluate the CD8 T cell subsets, expression of inhibitory receptors, and functionality of T cells in CCPs, PBMCs were isolated. The results showed that treatment of CCPs with the asymptomatic form of the disease induces an increase in the frequency of CD8 central memory T cells and terminal effector T cells, a decrease in the coexpression of inhibitory receptors, an improved Ag-specific CD8 T cell response exhibited by the individual production of IFN-γ or IL-2, and a multifunctional CD8 T cell profile of up to four functions (IFN-γIL-2PerforinGranzyme B). These findings suggest that, in CCPs, antiparasitic treatment improved the quality of Ag-specific CD8 T cell responses associated with a decrease in inhibitory receptor coexpression, which could serve as biomarkers for monitoring the effectiveness of antiparasitic treatment.

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

“…Furthermore, an association between therapeutic success of benznidazole (one of the two anti-parasitic drugs of approved use for the treatment of acute Chagas disease) in pediatric patients, and the loss of parasite-specific IFN-γ producing T cells was observed (132). Also, the treatment of chronic patients seems to restore T cell populations functionality and composition, in terms of state of activation and differentiation (132, 133). This evidence supports the relevance of persistent antigenic stimulation during chronic T. cruzi infection in the development of an inefficient T cell response in the long term.…”

A Parasite Biomarker Set for Evaluating Benznidazole Treatment Efficacy in Patients with Chronic Asymptomatic Trypanosoma cruzi Infection

“…These results showed that the treatment of Chagas patients with benznidazole modifies the humoral response pattern against these specific antigens, exhibiting different kinetics depending on whether the patient is in the asymptomatic or symptomatic stage of the disease (21,25). Relatedly, previous laboratory studies also showed that treatment leads to an improvement in the quality of the antigen-specific response of CD8 ϩ T cells in asymptomatic chronic Chagas disease patients (26). This improved response was associated with a decrease in the frequency of CD8 ϩ T cells coexpressing inhibitory receptors and an increase in the multifunctional capacity (cytokine and cytotoxic molecule expression) of these cells (26).…”

“…Relatedly, previous laboratory studies also showed that treatment leads to an improvement in the quality of the antigen-specific response of CD8 ϩ T cells in asymptomatic chronic Chagas disease patients (26). This improved response was associated with a decrease in the frequency of CD8 ϩ T cells coexpressing inhibitory receptors and an increase in the multifunctional capacity (cytokine and cytotoxic molecule expression) of these cells (26). These results are relevant because in T. cruzi infection, as in other chronic infectious diseases, it has been shown that persistent antigenic presence is associated with the gradual development of the dysfunction of CD8 ϩ T cells, which is linked to the expression of several inhibitory receptors that might negatively regulate the function of antigen-specific T cells and compromise pathogen control (27)(28)(29).…”

La respuesta inmunitaria adaptativa en la infección crónica por Trypanosoma cruzi

“…Los linfocitos T infiltrantes en miocardiopatía crónica expresan receptores inhibitorios (CTLA-4 y PD-1) indicadores de agotamiento celular (Argüello, et al, 2012). Vale la pena señalar que algunos de los cambios descritos son similares a los encontrados en linfocitos T de sangre periférica en pacientes con cardiopatía chagásica avanzada, los cuales también presentan características de agotamiento clonal, como la pérdida de la multifuncionalidad y la expresión de receptores inhibitorios (Giraldo, et al, 2013;Lasso, et al, 2015;Mateus, et al, 2017). Algunas de estas alteraciones fenotípicas y funcionales en los linfocitos T pueden revertirse con el tratamiento anti-parasitario (Mateus, et al, 2017).…”

“…Vale la pena señalar que algunos de los cambios descritos son similares a los encontrados en linfocitos T de sangre periférica en pacientes con cardiopatía chagásica avanzada, los cuales también presentan características de agotamiento clonal, como la pérdida de la multifuncionalidad y la expresión de receptores inhibitorios (Giraldo, et al, 2013;Lasso, et al, 2015;Mateus, et al, 2017). Algunas de estas alteraciones fenotípicas y funcionales en los linfocitos T pueden revertirse con el tratamiento anti-parasitario (Mateus, et al, 2017). El estudio de la respuesta inmunitaria contra T. cruzi sigue siendo un reto de la investigación actual, en parte por la compleja historia natural de la infección y las diferencias de la respuesta inmunitaria adaptativa en la fase aguda y la fase crónica de la infección, además de las variaciones gené-ticas del parásito.…”