Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses

Abstract

BackgroundChronic Chagas disease presents different clinical manifestations ranging from asymptomatic (namely indeterminate) to severe cardiac and/or digestive. Previous results have shown that the immune response plays an important role, although no all mechanisms are understood. Immunoregulatory mechanisms such as apoptosis are important for the control of Chagas disease, possibly affecting the morbidity in chronic clinical forms. Apoptosis has been suggested to be an important mechanism of cellular response during T. cruzi infection. We aimed to further understand the putative role of apoptosis in Chagas disease and its relation to the clinical forms of the disease.MethodsApoptosis of lymphocytes, under antigenic stimuli (soluble T. cruzi antigens – TcAg) where compared to that of non-stimulated cells. Apoptosis was evaluated using the expression of annexin and caspase 3+ by T cells and the percentage of cells positive evaluated by flow cytometry. In addition activation and T cell markers were used for the identification of TCD4+ and TCD8+ subpopulations. The presence of intracellular and plasma cytokines were also evaluated. Analysis of the activation status of the peripheral blood cells showed that patients with Chagas disease presented higher levels of activation determined by the expression of activation markers, after TcAg stimulation. PCR array were used to evaluate the contribution of this mechanism in specific cell populations from patients with different clinical forms of human Chagas disease.ResultsOur results showed a reduced proliferative response associated a high expression of T CD4+CD62L− cells in CARD patients when compared with IND group and NI individuals. We also observed that both groups of patients presented a significant increase of CD4+ and CD8+ T cell subsets in undergoing apoptosis after in vitro stimulation with T. cruzi antigens. In CARD patients, both CD4+ and CD8+ T cells expressing TNF-α were highly susceptible to undergo apoptosis after in vitro stimulation. Interestingly, the in vitro TcAg stimulation increased considerably the expression of cell death TNF/TNFR superfamily and Caspase family receptors genes in CARD patients.ConclusionsTaken together, our results suggest that apoptosis may be an important mechanism for the control of morbidity in T. cruzi infection by modulating the expression of apoptosis genes, the cytokine environment and/or killing of effector cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1523-1) contains supplementary material, which is available to authorized users.

Co‐infection with distinct Trypanosoma cruzi strains induces an activated immune response in human monocytes

“…The fact that we observed a decrease in double‐infected, as well as 3253 single‐infected monocytes after 72 hours of culture, suggests that this reduction is due to the high activation profile, consistent with the high intensity of expression of the activation molecules TLR‐2, HLA‐DR and a higher percentage of the pro‐inflammatory cytokine TNF observed in those cells. In fact, the decrease in infected cells was also accompanied by a decrease in TNF + cells, suggesting that these cells may undergo apoptosis, as previous studies have shown that TNF can induce apoptosis . We have also shown that T cruzi infection induces apoptosis in neutrophils, which is associated with TNF production .…”

Distinct Trypanosoma cruzi isolates induce activation and apoptosis of human neutrophils

“…Previous studies have shown that TNF is an apoptosis inducer in many different cell types [ 38 , 39 ]. It is noteworthy that the population of neutrophils in which we observed the higher rate of apoptosis (CFSE+) is also the one expressing higher TNF.…”

Efferocytosis of Pathogen-Infected Cells

“…Trypanosma cruzi infection induces lymphocyte apoptosis in both experimentally infected mice ( 122 , 123 ) and infected humans ( 124 ), and disease severity correlated with the degree of ex vivo apoptosis observed ( 124 , 125 ). Mouse experiments support the concept that phagocyte uptake of apoptotic T lymphocytes results in the establishment of an anti-inflammatory response dictated by TGF-β and prostaglandin PGE2 that fuels parasite persistence and disease ( 126 ).…”