T Lymphocytes from Chagasic Patients Are Activated but Lack Proliferative Capacity and Down-Regulate CD28 and CD3ζ

Abstract

BackgroundChronic persistent infections have been associated with T lymphocytes functional impairment. The aim of this study was to compare the activation status, the proliferative potential and the expression of CD28 and CD3ζ chain on T lymphocytes between chronic chagasic patients and uninfected controls.Methodology/Principal FindingsForty-two chronic chagasic patients, 28 healthy individuals and 32 non-chagasic cardiomyopathy donors were included. Peripheral blood was marked for CD3, CD4, CD8, HLA-DR, CD28, CD38 and intracellular CD3ζ. Peripheral blood mononuclear cells were stained with carboxyfluorescein diacetate succinimidylester and incubated with T. cruzi lysate or phytohemagglutinin for five days. Cells from 3 healthy controls were incubated with T. cruzi trypomastigotes separated with transwells; and the expression of CD3ζ chain and proliferation index was determined. Heart-infiltrating cells from two chronic chagasic patients were tested for the aforementioned cellular markers. Chagasic patients displayed higher frequencies of CD4+/HLA-DR+/CD38+ (8.1%±6.1) and CD8+/HLA-DR+/CD38+ (19.8±8.9) T cells in comparison with healthy (1.6±1.0; 10.6±8.0) and non-chagasic cardiomyopathy donors (2.9±2.9; 5.8±6.8). Furthermore, the percentage of CD4+ activated T cells was higher in chagasic patients with cardiac involvement. CD8+ T cells proliferation index in chagasic donors (1.7±0.3) was lower when compared with healthy (2.3±0.3) and non-chagasic cardiomyopathy individuals (3.1±1.1). The frequencies of CD4+/CD28+ and CD8+/CD28+ T cells, as well as the CD3ζbright/CD3ζdim% ratios in CD4+ and CD8+ were lower in chagasic patients when compared with both control groups. The CD3ζbright/CD3ζdim% ratio and proliferative indexes for CD4+ and CD8+ T lymphocytes decreased gradually in those cells cultivated with parasites and displayed lower values than those incubated with medium alone. Finally, heart-infiltrating T cells from two T. cruzi infected patients also expressed activation markers and down-regulate CD28 and CD3ζ.ConclusionsCD8+ T lymphocytes from chagasic donors displayed reduced proliferative capacity, which might be associated with CD3ζ down-regulation and diminished CD28 expression on CD4 T cells.

Inhibitory Receptor Expression on CD8+ T Cells Is Linked to Functional Responses against Trypanosoma cruzi Antigens in Chronic Chagasic Patients

“…Nonetheless, when two cytokines were evaluated, T. cruzi-specific CD8 + T cells in clinically compromised subjects displayed a functional profile of T cells secreting IFN-g alone with a low frequency of dual IFN-g + IL-2 + -secreting T cells (26). In addition, it has been shown that CD8 + T cell proliferation is diminished in chronic chagasic patients (CCP) compared with healthy donors (HD) and patients with nonchagasic cardiomyopathy (27). Moreover, an increase in the frequency of fully differentiated CD8 + T cells with attenuated cytokine effector functions has been observed in subjects presenting a severe form of this disease and in mouse models of chronic Chagas disease (CCD) (25,28,29).…”

T cells responding to Trypanosoma cruzi detected by membrane TNF‐α and CD154 in chagasic patients

“…Chronic chagasic patients displayed dysfunctional T cell responses characterized by increased frequency of terminally differentiated cells, monofunctional antigen‐specific T cell responses and progressive attenuation of cytokine production 7, 10, 21, 37. IFN‐γ secretion in T cells decreased with the severity of cardiac disease in both 24 CD4+ 7 and CD8+ 37 T cell subsets.…”

La respuesta inmunitaria adaptativa en la infección crónica por Trypanosoma cruzi

“…La mayoría de los estudios sobre inmunidad celular en estos individuos se hacen en sangre periférica y en tejido cardiaco, y los resultados se obtienen sobre todo mediante citometría de flujo e inmunohistoquímica, respectivamente. No obstante, en algunos estudios se han analizado linfocitos derivados de corazón utilizando citometría de flujo (Giraldo, et al, 2013).…”

“…Sin embargo, a pesar de expresar marcadores de activación, estas células proliferan menos en presencia de un mitógeno como la fitohemaglutinina (PHA). Usando un modelo in vitro, se demostró que los linfocitos T, tanto CD4+ como CD8+, provenientes de individuos no infectados disminuyeron drásticamente su proliferación en presencia de formas de tripomastigotes del parásito (Giraldo, et al, 2013). La poca respuesta de los linfocitos T en presencia del antígeno parasitario se ha asociado a una respuesta alterada a la IL-2 (Beltz & Kierszenbaum, 1988).…”

“…Anticuerpos con miocardiopatía chagásica, y no se observaron en tejidos cardiacos derivados del trasplante en pacientes con cardiopatía crónica no chagásica (Giraldo, et al, 2011(Giraldo, et al, & 2013. Dichos resultados sugieren que la alteración en la respuesta de los linfocitos T puede estar mediada por la persistencia del antígeno parasitario en los individuos infectados, lo cual altera la activación celular y contribuye a la patogenia en la enfermedad crónica (Figura 2).…”