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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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Proposed hypothesis for CD25High CD4+ Treg cells function on immunoregulation in chronic Chagas' disease.Several leukocyte subsets have been shown to play a role in immunoregulation during chronic infections. In this model, Chagas' disease patients with the indeterminate clinical form show Treg cells able to modulate the effectors' function of CD8+ T cells, in a microenvironment supported by cytotoxic NK-cells, Monocytes and CD4+ T cells producing regulatory cytokines (IL-10 and IL-10, IL-4, respectively). This immunological milieu contributes to controlling the parasitemia and regulating the immunopathology. On the other hand, Chagas' disease patients with cardiac and digestive clinical forms display insufficient modulation by Treg cells with activated CD8+ T cells besides monocytes and CD4+ T cells producing inflammatory cytokines (TNF-α and IFN-γ, respectively). This microenvironment triggers immunopathological events and leads to tissue damage in the absence of regulatory mechanisms and cytotoxic NK-cell functions.
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pntd-0000992-g004: Proposed hypothesis for CD25High CD4+ Treg cells function on immunoregulation in chronic Chagas' disease.Several leukocyte subsets have been shown to play a role in immunoregulation during chronic infections. In this model, Chagas' disease patients with the indeterminate clinical form show Treg cells able to modulate the effectors' function of CD8+ T cells, in a microenvironment supported by cytotoxic NK-cells, Monocytes and CD4+ T cells producing regulatory cytokines (IL-10 and IL-10, IL-4, respectively). This immunological milieu contributes to controlling the parasitemia and regulating the immunopathology. On the other hand, Chagas' disease patients with cardiac and digestive clinical forms display insufficient modulation by Treg cells with activated CD8+ T cells besides monocytes and CD4+ T cells producing inflammatory cytokines (TNF-α and IFN-γ, respectively). This microenvironment triggers immunopathological events and leads to tissue damage in the absence of regulatory mechanisms and cytotoxic NK-cell functions.

Mentions: Other studies have shown that IL-10 is an important cytokine involved in the suppressive function of Treg/Tr1 cells [36], [63]. Although there is no clear evidence for the effector function of this cell population in Chagas' disease, we observed a high percentage of CD25High CD4+ T cells from cardiac patients expressing CTLA-4, as well as an increase in the frequency of CD25High CD4+ T cells expressing IL-10 (Figure 1) with a simultaneous decrease in the frequency of IL-10 receptor in IND and CARD (Figure 2F). Therefore, it is possible that CD25High CD4+ Treg cells from IND patients may be important in controlling type 1 response to T. cruzi. Thus, a hypothesis to be further tested is that Treg cells, through expression of cIL-10, are beneficial to patients in the indeterminate clinical form by maintaining a balance between efficient effector cells that kill the parasites and avoiding the development of tissue immunopathology. On the other hand, in CARD patients, these cells are not sufficient and/or competent to control the inflammatory process mediated by high levels of activated CD8+ HLA-DR+ T cells as previously observed in the peripheral blood [10] and the inflammatory infiltrate of cardiac lesions [1], [64]. Thus, it is likely that CD25High CD4+ T cells use different mechanisms to regulate the immune response during Chagas' disease and that the host-parasite interactions may be influenced by the ratio of regulatory/effectors T cells. Based on our observations, the model presented in Figure 4 may explain the putative mechanisms involved in the control and induction of pathology in Chagas' disease and is being used by our group as the test model of our hypotheses. We argue that the generation of protection or pathogenic responses in Chagas' disease is highly influenced by the suggested balance of this complex immune response induced by T. cruzi as previously shown by our group and others. Therefore, cardiac patients have specific cell populations involved in the establishment of an inflammatory cytokine profile and lack of control of the immune response. On the other hand, indeterminate patients have an effective, and possibly transitory, control of the response to the infection mediated by regulatory and effector T cells.


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)

Proposed hypothesis for CD25High CD4+ Treg cells function on immunoregulation in chronic Chagas' disease.Several leukocyte subsets have been shown to play a role in immunoregulation during chronic infections. In this model, Chagas' disease patients with the indeterminate clinical form show Treg cells able to modulate the effectors' function of CD8+ T cells, in a microenvironment supported by cytotoxic NK-cells, Monocytes and CD4+ T cells producing regulatory cytokines (IL-10 and IL-10, IL-4, respectively). This immunological milieu contributes to controlling the parasitemia and regulating the immunopathology. On the other hand, Chagas' disease patients with cardiac and digestive clinical forms display insufficient modulation by Treg cells with activated CD8+ T cells besides monocytes and CD4+ T cells producing inflammatory cytokines (TNF-α and IFN-γ, respectively). This microenvironment triggers immunopathological events and leads to tissue damage in the absence of regulatory mechanisms and cytotoxic NK-cell functions.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0000992-g004: Proposed hypothesis for CD25High CD4+ Treg cells function on immunoregulation in chronic Chagas' disease.Several leukocyte subsets have been shown to play a role in immunoregulation during chronic infections. In this model, Chagas' disease patients with the indeterminate clinical form show Treg cells able to modulate the effectors' function of CD8+ T cells, in a microenvironment supported by cytotoxic NK-cells, Monocytes and CD4+ T cells producing regulatory cytokines (IL-10 and IL-10, IL-4, respectively). This immunological milieu contributes to controlling the parasitemia and regulating the immunopathology. On the other hand, Chagas' disease patients with cardiac and digestive clinical forms display insufficient modulation by Treg cells with activated CD8+ T cells besides monocytes and CD4+ T cells producing inflammatory cytokines (TNF-α and IFN-γ, respectively). This microenvironment triggers immunopathological events and leads to tissue damage in the absence of regulatory mechanisms and cytotoxic NK-cell functions.
Mentions: Other studies have shown that IL-10 is an important cytokine involved in the suppressive function of Treg/Tr1 cells [36], [63]. Although there is no clear evidence for the effector function of this cell population in Chagas' disease, we observed a high percentage of CD25High CD4+ T cells from cardiac patients expressing CTLA-4, as well as an increase in the frequency of CD25High CD4+ T cells expressing IL-10 (Figure 1) with a simultaneous decrease in the frequency of IL-10 receptor in IND and CARD (Figure 2F). Therefore, it is possible that CD25High CD4+ Treg cells from IND patients may be important in controlling type 1 response to T. cruzi. Thus, a hypothesis to be further tested is that Treg cells, through expression of cIL-10, are beneficial to patients in the indeterminate clinical form by maintaining a balance between efficient effector cells that kill the parasites and avoiding the development of tissue immunopathology. On the other hand, in CARD patients, these cells are not sufficient and/or competent to control the inflammatory process mediated by high levels of activated CD8+ HLA-DR+ T cells as previously observed in the peripheral blood [10] and the inflammatory infiltrate of cardiac lesions [1], [64]. Thus, it is likely that CD25High CD4+ T cells use different mechanisms to regulate the immune response during Chagas' disease and that the host-parasite interactions may be influenced by the ratio of regulatory/effectors T cells. Based on our observations, the model presented in Figure 4 may explain the putative mechanisms involved in the control and induction of pathology in Chagas' disease and is being used by our group as the test model of our hypotheses. We argue that the generation of protection or pathogenic responses in Chagas' disease is highly influenced by the suggested balance of this complex immune response induced by T. cruzi as previously shown by our group and others. Therefore, cardiac patients have specific cell populations involved in the establishment of an inflammatory cytokine profile and lack of control of the immune response. On the other hand, indeterminate patients have an effective, and possibly transitory, control of the response to the infection mediated by regulatory and effector T cells.

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