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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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Phenotypic analysis of CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Phenotypic features of 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 for a range of phenotypic features of CD25High CD4+ 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 as the percentage of positive cells within CD25High CD4+ cells including those expressing adhesion molecules CD62L (D) and CD54 (B), co-stimulatory receptors CD40L (A) and CTLA-4 (E), activation marker CD69 (C) and regulatory receptor IL-10R (F). 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 that T. cruzi antigens triggered an overall change in the phenotypic features of CD25High CD4+ cells towards lower frequency of CD62L+ and IL-10R+ cells besides increased levels of CD54+, CD40L+, and CD69+ cells in both IND and CARD groups. Although T. cruzi antigens were able to induce higher levels of CTLA-4 in both groups of chagasic patients (IND and CARD), the impact of T. cruzi antigens was more pronounced in CARD, leading to higher frequency of CTLA-4+ cells in comparison to NI. Adapted from [20].
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pntd-0000992-g002: Phenotypic analysis of CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Phenotypic features of 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 for a range of phenotypic features of CD25High CD4+ 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 as the percentage of positive cells within CD25High CD4+ cells including those expressing adhesion molecules CD62L (D) and CD54 (B), co-stimulatory receptors CD40L (A) and CTLA-4 (E), activation marker CD69 (C) and regulatory receptor IL-10R (F). 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 that T. cruzi antigens triggered an overall change in the phenotypic features of CD25High CD4+ cells towards lower frequency of CD62L+ and IL-10R+ cells besides increased levels of CD54+, CD40L+, and CD69+ cells in both IND and CARD groups. Although T. cruzi antigens were able to induce higher levels of CTLA-4 in both groups of chagasic patients (IND and CARD), the impact of T. cruzi antigens was more pronounced in CARD, leading to higher frequency of CTLA-4+ cells in comparison to NI. Adapted from [20].

Mentions: With the objective of better illustrating the differences in this T cell population, we have further characterized the CD25High CD4+ Treg cells after in vitro exposure of whole blood to T. cruzi antigens. As a result, it was observed that CD25High CD4+ Treg cells of chagasic patients express a number of cell surface markers that have been associated with activation and migration. Human CD25High CD4+ Treg cells from IND and CARD patients presented an increased expression of CD40L, CD54, and CD69 (Figure 2A, B, and C, respectively) and a decreased expression of CD62L (Figure 2D) in the peripheral blood. Baecher-Allan and colleagues [15] first suggested that the CD25High CD4+ T cells may exist in a semi-activated state in vivo, expressing a number of surface antigens that are usually associated with activated T cells. Thus, Treg cells may be primed for an anamnestic response upon re-encountering the parasite antigens. Previous reports have shown increased levels of adhesion molecules (CD54 and LFA-1) on regulatory cell subsets [14], [44]–[46], suggesting that these cells are able to penetrate into inflamed tissues and may act directly at the sites of inflamation [16], [47]–[49]. Our results are in agreement with these findings and we suggest that in Chagas' disease CD25High CD4+ T cells can migrate to the tissues and control the severe inflammatory response in individuals with the IND clinical form of the disease. Additional analyses are currently being undertaken by our group to further support this hypothesis.


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)

Phenotypic analysis of CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Phenotypic features of 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 for a range of phenotypic features of CD25High CD4+ 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 as the percentage of positive cells within CD25High CD4+ cells including those expressing adhesion molecules CD62L (D) and CD54 (B), co-stimulatory receptors CD40L (A) and CTLA-4 (E), activation marker CD69 (C) and regulatory receptor IL-10R (F). 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 that T. cruzi antigens triggered an overall change in the phenotypic features of CD25High CD4+ cells towards lower frequency of CD62L+ and IL-10R+ cells besides increased levels of CD54+, CD40L+, and CD69+ cells in both IND and CARD groups. Although T. cruzi antigens were able to induce higher levels of CTLA-4 in both groups of chagasic patients (IND and CARD), the impact of T. cruzi antigens was more pronounced in CARD, leading to higher frequency of CTLA-4+ cells in comparison to NI. Adapted from [20].
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0000992-g002: Phenotypic analysis of CD25High CD4+ regulatory T cells in the peripheral blood from chagasic patients.Phenotypic features of 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 for a range of phenotypic features of CD25High CD4+ 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 as the percentage of positive cells within CD25High CD4+ cells including those expressing adhesion molecules CD62L (D) and CD54 (B), co-stimulatory receptors CD40L (A) and CTLA-4 (E), activation marker CD69 (C) and regulatory receptor IL-10R (F). 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 that T. cruzi antigens triggered an overall change in the phenotypic features of CD25High CD4+ cells towards lower frequency of CD62L+ and IL-10R+ cells besides increased levels of CD54+, CD40L+, and CD69+ cells in both IND and CARD groups. Although T. cruzi antigens were able to induce higher levels of CTLA-4 in both groups of chagasic patients (IND and CARD), the impact of T. cruzi antigens was more pronounced in CARD, leading to higher frequency of CTLA-4+ cells in comparison to NI. Adapted from [20].
Mentions: With the objective of better illustrating the differences in this T cell population, we have further characterized the CD25High CD4+ Treg cells after in vitro exposure of whole blood to T. cruzi antigens. As a result, it was observed that CD25High CD4+ Treg cells of chagasic patients express a number of cell surface markers that have been associated with activation and migration. Human CD25High CD4+ Treg cells from IND and CARD patients presented an increased expression of CD40L, CD54, and CD69 (Figure 2A, B, and C, respectively) and a decreased expression of CD62L (Figure 2D) in the peripheral blood. Baecher-Allan and colleagues [15] first suggested that the CD25High CD4+ T cells may exist in a semi-activated state in vivo, expressing a number of surface antigens that are usually associated with activated T cells. Thus, Treg cells may be primed for an anamnestic response upon re-encountering the parasite antigens. Previous reports have shown increased levels of adhesion molecules (CD54 and LFA-1) on regulatory cell subsets [14], [44]–[46], suggesting that these cells are able to penetrate into inflamed tissues and may act directly at the sites of inflamation [16], [47]–[49]. Our results are in agreement with these findings and we suggest that in Chagas' disease CD25High CD4+ T cells can migrate to the tissues and control the severe inflammatory response in individuals with the IND clinical form of the disease. Additional analyses are currently being undertaken by our group to further support this hypothesis.

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