Profile of Central and Effector Memory T Cells in the Progression of Chronic Human Chagas Disease

Abstract

BackgroundChronic Chagas disease presents several different clinical manifestations ranging from asymptomatic to severe cardiac and/or digestive clinical forms. Several studies have demonstrated that immunoregulatory mechanisms are important processes for the control of the intense immune activity observed in the chronic phase. T cells play a critical role in parasite specific and non-specific immune response elicited by the host against Trypanosoma cruzi. Specifically, memory T cells, which are basically classified as central and effector memory cells, might have a distinct migratory activity, role and function during the human Chagas disease.Methodology/Principal FindingsBased on the hypothesis that the disease severity in humans is correlated to the quality of immune responses against T. cruzi, we evaluated the memory profile of peripheral CD4+ and CD8+ T lymphocytes as well as its cytokine secretion before and after in vitro antigenic stimulation. We evaluated cellular response from non-infected individuals (NI), patients with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas disease. The expression of CD45RA, CD45RO and CCR7 surface molecules was determined on CD4+ and CD8+ T lymphocytes; the pattern of intracellular cytokines (IFN-γ, IL-10) synthesized by naive and memory cells was determined by flow cytometry. Our results revealed that IND and CARD patients have relatively lower percentages of naive (CD45RAhigh) CD4+ and CD8+ T cells. However, statistical analysis of ex-vivo profiles of CD4+ T cells showed that IND have lower percentage of CD45RAhigh in relation to non-infected individuals, but not in relation to CARD. Elevated percentages of memory (CD45ROhigh) CD4+ T cells were also demonstrated in infected individuals, although statistically significant differences were only observed between IND and NI groups. Furthermore, when we analyzed the profile of secreted cytokines, we observed that CARD patients presented a significantly higher percentage of CD8+CD45RAhigh IFN-γ-producing cells in control cultures and after antigen pulsing with soluble epimastigote antigens.ConclusionsBased on a correlation between the frequency of IFN-γ producing CD8+ T cells in the T cell memory compartment and the chronic chagasic myocarditis, we propose that memory T cells can be involved in the induction of the development of the severe clinical forms of the Chagas disease by mechanisms modulated by IFN-γ. Furthermore, we showed that individuals from IND group presented more TCM CD4+ T cells, which may induce a regulatory mechanism to protect the host against the exacerbated inflammatory response elicited by the infection.

Evaluation of the immune response against Trypanosoma cruzi cytosolic tryparedoxin peroxidase in human natural infection

“…It is tempting to discard the naive population in the response raised against c‐TXNPx in asymptomatic patients, given the lack of proliferation detected in PBMC from non‐infected individuals. In fact, an augmentation in central memory T cells was detected within the CD4 + memory T‐cell population from asymptomatic patients not only ex vivo but also upon T. cruzi lysate stimulation . However, it is important to mention that a switch in memory compartment towards central but not effector T cells is not always observed in recall responses after in vitro stimulation with T. cruzi proteins …”

Trypanosoma cruzi -Induced Activation of Functionally Distinct αβ and γδ CD4 − CD8 − T Cells in Individuals with Polar Forms of Chagas' Disease

“…Studies performed by us and other groups have shown that major T-cell populations, defined by the expression of CD4 and CD8, display phenotypic and functional differences in individuals with different clinical forms of Chagas' disease. To this end, the frequencies of memory cells, as well as senescent cells, have been associated with the chronic cardiac form of Chagas' disease (1,2,23). While these studies have provided critical information, the determination of the contribution of distinct subpopulations to the immunoregulation and functional activities, as well as the antigens that lead to their activation, is critical for the understanding the mechanisms of generation of pathogenic versus protective responses in Chagas' disease.…”

Cytokine Levels in Serious Cardiopathy of Chagas Disease After In Vitro Stimulation with Recombinant Antigens from Trypanosoma cruzi

“…The detection of these cytokines produced by CD8+ T cells suggests that CRA induces an inflammatory response, which is related to the severity of cardiac damage. In fact, studies have pointed to the role of CD8+ T lymphocytes in inflammatory infiltration of cardiac fibres in patients with severe cardiopathy, with secretion of TNF-a and IFN-c possibly exacerbating inflammation and tissue damage [5,[21][22][23][24][25]. In this way, our results suggest that IFN-c and TNF-a cytokines produced by CD8+ T cells of whole blood may be used as biological markers for these clinical forms if a longitudinal study with follow-up of the IND group is performed.…”