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Regulatory T cells phenotype in different clinical forms of Chagas' disease.

de Araújo FF, Vitelli-Avelar DM, Teixeira-Carvalho A, Antas PR, Assis Silva Gomes J, Sathler-Avelar R, Otávio Costa Rocha M, Elói-Santos SM, Pinho RT, Correa-Oliveira R, Martins-Filho OA - PLoS Negl Trop Dis (2011)

Bottom Line: Moreover, there was an increase in the frequency of the population of Foxp3+ CD25(High)CD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25(High) CD4+ cells that expressed CTLA-4.These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients.However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brasil.

ABSTRACT
CD25(High) CD4+ regulatory T cells (Treg cells) have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In this review, we summarize data obtained by the investigation of Treg cells in different clinical forms of Chagas' disease. Ex vivo immunophenotyping of whole blood, as well as after stimulation with Trypanosoma cruzi antigens, demonstrated that individuals in the indeterminate (IND) clinical form of the disease have a higher frequency of Treg cells, suggesting that an expansion of those cells could be beneficial, possibly by limiting strong cytotoxic activity and tissue damage. Additional analysis demonstrated an activated status of Treg cells based on low expression of CD62L and high expression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. cruzi antigenic stimulation. Moreover, there was an increase in the frequency of the population of Foxp3+ CD25(High)CD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25(High) CD4+ cells that expressed CTLA-4. These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients. However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease. These data suggest that Treg cells may play an important role in controlling the immune response in Chagas' disease and the balance between regulatory and effector T cells may be important for the progression and development of the disease. Additional detailed analysis of the mechanisms on how these cells are activated and exert their function will certainly give insights for the rational design of procedure to achieve the appropriate balance between protection and pathology during parasite infections.

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Related in: MedlinePlus

Analysis of IL-10+ CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Frequency of regulatory T cells and intracytoplasmic IL-10 (cIL-10) levels in CD25High CD4+ cells from patients with distinct clinical forms of Chagas' disease (IND, light gray box; CARD, dark gray box) and non-infected individuals (NI, white box) following short-term in vitro stimulation of whole blood samples with T. cruzi antigens. Baseline levels of CD25High CD4+ and cIL-10+ T cells were obtained from control cultures (CC) maintained under the same conditions (22 h incubation at 37°C, CO2 humidified incubator). The results are expressed in box plot format for CD25High CD4+ (left panels) and cIL-10+ T cells (right panels). The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and, therefore, contains the middle half of the score in the distribution. The median is shown as a line across the box. Therefore, 1:4 of the distribution is between this line and the bottom or the top of the box. Significant differences are identified by connecting lines for comparisons between CC and Ag, and highlighted the ability of T. cruzi antigens to trigger enhanced levels of CD25High CD4+ and cIL-10+ T cells in both IND and CARD groups. Significant differences between clinical groups are identified by asterisks as compared to NI.
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pntd-0000992-g001: Analysis of IL-10+ CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Frequency of regulatory T cells and intracytoplasmic IL-10 (cIL-10) levels in CD25High CD4+ cells from patients with distinct clinical forms of Chagas' disease (IND, light gray box; CARD, dark gray box) and non-infected individuals (NI, white box) following short-term in vitro stimulation of whole blood samples with T. cruzi antigens. Baseline levels of CD25High CD4+ and cIL-10+ T cells were obtained from control cultures (CC) maintained under the same conditions (22 h incubation at 37°C, CO2 humidified incubator). The results are expressed in box plot format for CD25High CD4+ (left panels) and cIL-10+ T cells (right panels). The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and, therefore, contains the middle half of the score in the distribution. The median is shown as a line across the box. Therefore, 1:4 of the distribution is between this line and the bottom or the top of the box. Significant differences are identified by connecting lines for comparisons between CC and Ag, and highlighted the ability of T. cruzi antigens to trigger enhanced levels of CD25High CD4+ and cIL-10+ T cells in both IND and CARD groups. Significant differences between clinical groups are identified by asterisks as compared to NI.

Mentions: It has been previously described that regulatory T cells can suppress the immune response by producing anti-inflammatory cytokines, such as IL-10 and TGF-β [36]. In an attempt to better characterize these cells in Chagas' disease, we investigated whether CD25High CD4+ Treg in the peripheral blood of chagasic patients are IL-10 producers [20]. We observed an increased frequency of cytoplasmic (c) IL-10+ CD25High CD4+ Treg cells in both IND and CARD individuals after in vitro recall responses induced by exposure to T. cruzi antigens (Figure 1). It is interesting to note that our group and others have already described an association between the secretion of IL-10 and the control of immunopathology [3], [4],[9],[34],[37]–[39], contrasting with the observed increase in IL-10+ CD25High CD4+ Treg cells in CARD. However, it is important to mention that the number of positive cells for this cytokine is higher in IND individuals (unpublished data). The differences mentioned may be explained by increasing evidence that supports the hypothesis that the fine balance of inflammatory and regulatory cytokines derived from distinct T cell sources is the key factor for the resulting immune-mediated mechanisms that drive the disease outcome [3]. In order to confirm if CD25High CD4+ T cells are correlated with improved cardiac function and, thus, a possible protective role in Chagas' disease, we performed a correlation analysis between the frequency of these cells and two clinical parameters of cardiac function: left ventricular ejection fraction (LVEF) and left ventricular diastolic diameter (LVDD). These distinct clinical parameters are directly and inversely correlated with better cardiac function, respectively. A significant positive correlation was seen between higher LVEF and higher frequency of CD25High CD4+ T cells and a significant negative correlation was seen between lower LVDD and higher frequency of CD25High CD4+ T cells. These data suggest that CD25High CD4+ T cells display an import immunoregulatory role that leads to maintenance of better cardiac function in IND patients (unpublished data).


Regulatory T cells phenotype in different clinical forms of Chagas' disease.

de Araújo FF, Vitelli-Avelar DM, Teixeira-Carvalho A, Antas PR, Assis Silva Gomes J, Sathler-Avelar R, Otávio Costa Rocha M, Elói-Santos SM, Pinho RT, Correa-Oliveira R, Martins-Filho OA - PLoS Negl Trop Dis (2011)

Analysis of IL-10+ CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Frequency of regulatory T cells and intracytoplasmic IL-10 (cIL-10) levels in CD25High CD4+ cells from patients with distinct clinical forms of Chagas' disease (IND, light gray box; CARD, dark gray box) and non-infected individuals (NI, white box) following short-term in vitro stimulation of whole blood samples with T. cruzi antigens. Baseline levels of CD25High CD4+ and cIL-10+ T cells were obtained from control cultures (CC) maintained under the same conditions (22 h incubation at 37°C, CO2 humidified incubator). The results are expressed in box plot format for CD25High CD4+ (left panels) and cIL-10+ T cells (right panels). The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and, therefore, contains the middle half of the score in the distribution. The median is shown as a line across the box. Therefore, 1:4 of the distribution is between this line and the bottom or the top of the box. Significant differences are identified by connecting lines for comparisons between CC and Ag, and highlighted the ability of T. cruzi antigens to trigger enhanced levels of CD25High CD4+ and cIL-10+ T cells in both IND and CARD groups. Significant differences between clinical groups are identified by asterisks as compared to NI.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3104959&req=5

pntd-0000992-g001: Analysis of IL-10+ CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Frequency of regulatory T cells and intracytoplasmic IL-10 (cIL-10) levels in CD25High CD4+ cells from patients with distinct clinical forms of Chagas' disease (IND, light gray box; CARD, dark gray box) and non-infected individuals (NI, white box) following short-term in vitro stimulation of whole blood samples with T. cruzi antigens. Baseline levels of CD25High CD4+ and cIL-10+ T cells were obtained from control cultures (CC) maintained under the same conditions (22 h incubation at 37°C, CO2 humidified incubator). The results are expressed in box plot format for CD25High CD4+ (left panels) and cIL-10+ T cells (right panels). The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and, therefore, contains the middle half of the score in the distribution. The median is shown as a line across the box. Therefore, 1:4 of the distribution is between this line and the bottom or the top of the box. Significant differences are identified by connecting lines for comparisons between CC and Ag, and highlighted the ability of T. cruzi antigens to trigger enhanced levels of CD25High CD4+ and cIL-10+ T cells in both IND and CARD groups. Significant differences between clinical groups are identified by asterisks as compared to NI.
Mentions: It has been previously described that regulatory T cells can suppress the immune response by producing anti-inflammatory cytokines, such as IL-10 and TGF-β [36]. In an attempt to better characterize these cells in Chagas' disease, we investigated whether CD25High CD4+ Treg in the peripheral blood of chagasic patients are IL-10 producers [20]. We observed an increased frequency of cytoplasmic (c) IL-10+ CD25High CD4+ Treg cells in both IND and CARD individuals after in vitro recall responses induced by exposure to T. cruzi antigens (Figure 1). It is interesting to note that our group and others have already described an association between the secretion of IL-10 and the control of immunopathology [3], [4],[9],[34],[37]–[39], contrasting with the observed increase in IL-10+ CD25High CD4+ Treg cells in CARD. However, it is important to mention that the number of positive cells for this cytokine is higher in IND individuals (unpublished data). The differences mentioned may be explained by increasing evidence that supports the hypothesis that the fine balance of inflammatory and regulatory cytokines derived from distinct T cell sources is the key factor for the resulting immune-mediated mechanisms that drive the disease outcome [3]. In order to confirm if CD25High CD4+ T cells are correlated with improved cardiac function and, thus, a possible protective role in Chagas' disease, we performed a correlation analysis between the frequency of these cells and two clinical parameters of cardiac function: left ventricular ejection fraction (LVEF) and left ventricular diastolic diameter (LVDD). These distinct clinical parameters are directly and inversely correlated with better cardiac function, respectively. A significant positive correlation was seen between higher LVEF and higher frequency of CD25High CD4+ T cells and a significant negative correlation was seen between lower LVDD and higher frequency of CD25High CD4+ T cells. These data suggest that CD25High CD4+ T cells display an import immunoregulatory role that leads to maintenance of better cardiac function in IND patients (unpublished data).

Bottom Line: Moreover, there was an increase in the frequency of the population of Foxp3+ CD25(High)CD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25(High) CD4+ cells that expressed CTLA-4.These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients.However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brasil.

ABSTRACT
CD25(High) CD4+ regulatory T cells (Treg cells) have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In this review, we summarize data obtained by the investigation of Treg cells in different clinical forms of Chagas' disease. Ex vivo immunophenotyping of whole blood, as well as after stimulation with Trypanosoma cruzi antigens, demonstrated that individuals in the indeterminate (IND) clinical form of the disease have a higher frequency of Treg cells, suggesting that an expansion of those cells could be beneficial, possibly by limiting strong cytotoxic activity and tissue damage. Additional analysis demonstrated an activated status of Treg cells based on low expression of CD62L and high expression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. cruzi antigenic stimulation. Moreover, there was an increase in the frequency of the population of Foxp3+ CD25(High)CD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25(High) CD4+ cells that expressed CTLA-4. These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients. However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease. These data suggest that Treg cells may play an important role in controlling the immune response in Chagas' disease and the balance between regulatory and effector T cells may be important for the progression and development of the disease. Additional detailed analysis of the mechanisms on how these cells are activated and exert their function will certainly give insights for the rational design of procedure to achieve the appropriate balance between protection and pathology during parasite infections.

Show MeSH
Related in: MedlinePlus