Foxp3+CD25high CD4+ regulatory T cells from indeterminate patients with Chagas disease can suppress the effector cells and cytokines and reveal altered correlations with disease severity

Araújo, Fernanda Fortes de; Corrêa-Oliveira, Rodrigo; Rocha, Manoel Otávio Costa; Chaves, Ana Cristina; Fiuza, Jacqueline Araújo; Fares, Rafaelle Christine Gomes; Ferreira, Karine Silvestre; Nunes, Maria Carmo P.; Keesen, Tatjana Souza Lima; Damasio, Marcos; Teixeira-Carvalho, Andréa; Gomes, Juliana de Assis Silva

doi:10.1016/j.imbio.2012.04.008

Cited by 65 publications

(71 citation statements)

References 51 publications

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“…Our group previously showed the essential role of immune cells, such as monocytes (39) and lymphocytes (18,40), in Chagas disease pathogenesis. In the present study, we observed that CD4 ϩ and CD8…”

Section: Discussionmentioning

confidence: 95%

“…The patients with Chagas disease who agreed to participate in this study were identified and selected at the Referral Outpatient Center for Chagas Disease at the Clinical Hospital of the Federal University of Minas Gerais (UFMG), Minas Gerais, Brazil, and at Evandro Chagas Clinical Research Institute (IPEC) at Fundação Oswaldo Cruz-Rio de Janeiro (FIOCRUZ-RJ), Rio de Janeiro, Brazil. Patients who consented to participate in this study were enrolled in a prospective cohort study initiated 15 years ago as previously described (18). The patients were grouped as indeterminate (IND) and cardiac (CARD) patients, as previ-ously reported (5,6 Serum MMP-2 and MMP-9 measurement.…”

Section: Methodsmentioning

confidence: 99%

“…The Cytometric Bead Array (CBA) immunoassay kit (BD Biosciences, USA) was used for TNF-␣ and IL-1␤ measurements as recommended by the manufacturer and as previously described (18,20). Data were acquired in a FACSCalibur flow cytometer (Becton, Dickinson), and the analyses were performed using CBA software (Becton, Dickinson).…”

Section: Methodsmentioning

confidence: 99%

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Matrix Metalloproteinases 2 and 9 Are Differentially Expressed in Patients with Indeterminate and Cardiac Clinical Forms of Chagas Disease

et al. 2013

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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Matrix Metalloproteinases 2 and 9 Are Differentially Expressed in Patients with Indeterminate and Cardiac Clinical Forms of Chagas Disease

et al. 2013

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“…Depletion of CD4 ϩ CD25 ϩ T cells did not correlate with an increase in CD8 ϩ T cells in tissue or even a change in parasitemia in the acute stage of the infection (52). In contrast to this, studies conducted with patients showed that high numbers of CD4 ϩ CD25 ϩ Foxp3 ϩ T cells secreting IL-10 and IL-17 correlated with the absence of cardiac pathology, whereas in patients with chronic cardiac disease the dominant cytokines were IL-6, IFN-␥, and tumor necrosis factor alpha (TNF-␣), thereby suggesting a protective role for Treg cells in cardiac pathology (53). Further studies are necessary to identify the cells producing IL-10 after vaccination.…”

Section: Discussionmentioning

confidence: 98%

Tc52 Amino-Terminal-Domain DNA Carried by Attenuated Salmonella enterica Serovar Typhimurium Induces Protection against a Trypanosoma cruzi Lethal Challenge

et al. 2014

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In this work we immunized mice with DNA encoding full-length Tc52 or its amino-or carboxy-terminal (N-and C-term, respectively) domain carried by attenuated Salmonella as a DNA delivery system. As expected, Salmonella-mediated DNA delivery resulted in low antibody titers and a predominantly Th1 response, as shown by the ratio of IgG2a/IgG1-specific antibodies. Despite modest expression of Tc52 in trypomastigotes, the antibodies elicited by vaccination were able to mediate lysis of the trypomastigotes in the presence of complement and inhibit their invasion of mammal cells in vitro. The strongest functional activity was observed with sera from mice immunized with Salmonella carrying the N-term domain (SN-term), followed by Tc52 (STc52), and the C-term domain (SC-term). All immunized groups developed strong cellular responses, with predominant activation of Th1 cells. However, mice immunized with SN-term showed higher levels of interleukin-10 (IL-10), counterbalancing the inflammatory reaction, and also strong activation of Tc52-specific gamma interferon-positive (IFN-␥ ؉ ) CD8 ؉ T cells. In agreement with this, although all prototypes conferred protection against infection, immunization with SN-term promoted greater protection than that with SC-term for all parameters tested and slightly better protection than that with STc52, especially in the acute stage of infection. We conclude that the N-terminal domain of Tc52 is the section of the protein that confers maximal protection against infection and propose it as a promising candidate for vaccine development.

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“…Pathological studies in patients and experimental models support the concept that parasite persistence (low-grade) in the myocardial tissues is the primary determinant of CM (24). Genetic studies in CM cohorts suggest that patients exhibiting lower frequencies of IL-10-producing monocytes (25), IL-10-producing double-negative Υd T cells (26), FoxP3 + CD25 + regulatory T cells (27) and IL-17-producing T cells (28) are more susceptible to chronic myocardiopathy, most likely reflecting inefficient regulation of heartinfiltrating TNF-a-producing effector CD8 + T cells (29,30). Beyond immunoregulatory dysfunctions, it is still unclear why patients with severe CM present conspicuous microvascular derangement in the myocardium (31).…”

mentioning

confidence: 97%

C5a and Bradykinin Receptor Cross-Talk Regulates Innate and Adaptive Immunity in Trypanosoma cruzi Infection

Schmitz

Almeida

Svensjö

et al. 2014

The Journal of Immunology

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Complement and the kallikrein–kinin cascade system are both activated in injured tissues. Little is known about their partnership in the immunopathogenesis of Chagas disease, the chronic infection caused by the intracellular protozoan Trypanosoma cruzi. In this study, we show that pharmacological targeting of the C5a receptor (C5aR) or the bradykinin B2 receptor (B2R) inhibited plasma leakage in hamster cheek pouch topically exposed to tissue culture trypomastigotes (TCTs). Further, angiotensin-converting enzyme inhibitors potentiated TCT-evoked paw edema in BALB/c, C57BL/6, and C5-deficient A/J mice through activation of joint pathways between C5aR/B2R or C3aR/B2R. In addition to generation of C5a and kinins via parasite-derived cruzipain, we demonstrate that macrophages internalize TCTs more efficiently through joint activation of C5aR/B2R. Furthermore, we found that C5aR targeting markedly reduces NO production and intracellular parasitism in macrophages. We then studied the impact of C5aR/B2R cross-talk in TCT infection on the development of adaptive immunity. We found that IL-12p40/70 expression was blunted in splenic dendritic cells by blocking either C5aR or B2R, suggesting that codominant signaling via C5aR and B2R fuels production of the Th1-polarizing cytokine. Finally, we assessed the impact of kinins and C5a liberated in parasite-laden tissues on Th cell differentiation. As predicted, BALB/c mice pretreated with angiotensin-converting enzyme inhibitors potentiated IFN-γ production by Ag-specific T cells via C5aR/B2R cross-talk. Interestingly, we found that B2R targeting upregulated IL-10 secretion, whereas C5aR blockade vigorously stimulated IL-4 production. In summary, we describe a novel pathway by which C5aR/B2R cross-talk couples transendothelial leakage of plasma proteins to the cytokine circuitry that coordinates antiparasite immunity.

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Foxp3+CD25high CD4+ regulatory T cells from indeterminate patients with Chagas disease can suppress the effector cells and cytokines and reveal altered correlations with disease severity

Cited by 65 publications

References 51 publications

Matrix Metalloproteinases 2 and 9 Are Differentially Expressed in Patients with Indeterminate and Cardiac Clinical Forms of Chagas Disease

Matrix Metalloproteinases 2 and 9 Are Differentially Expressed in Patients with Indeterminate and Cardiac Clinical Forms of Chagas Disease

Tc52 Amino-Terminal-Domain DNA Carried by Attenuated Salmonella enterica Serovar Typhimurium Induces Protection against a Trypanosoma cruzi Lethal Challenge

C5a and Bradykinin Receptor Cross-Talk Regulates Innate and Adaptive Immunity in Trypanosoma cruzi Infection

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