Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi

Egui, Adriana; Lasso, Paola; Thomas, M. Carmen; Carrilero, Bartolomé; González, John Mario; Cuéllar, Adriana; Segovia, Manuel; Puerta, Concepción J.; López, Manuel Carlos

doi:10.1371/journal.pntd.0005627

Cited by 11 publications

(9 citation statements)

References 36 publications

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“…cruzi soluble antigens ( Tc SA) were required to carry out the in vitro stimulation performed in this study. For this reason, rhesus monkey kidney epithelial cells (LLC-MK2 line; CCL-7, Manassas, VA) were cultured in RPMI-1640 supplemented with 2 mM L-glutamine (Gibco), 10% iFBS and 50 μg/mL gentamicin (Thermo Fisher Scientific, Waltham, Massachusetts, USA) at 37°C in 5% CO 2 according to a previously described protocol [ 28 ]. Infection of the LLC-MK2 semiconfluent monolayers was performed with the trypomastigote form of the Y strain of T .…”

Section: Study Population Materials and Methodsmentioning

confidence: 99%

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

et al. 2021

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Background Signs of senescence and the late stages of differentiation associated with the more severe forms of Chagas disease have been described in the Trypanosoma cruzi antigen-specific CD4+ T-cell population. However, the mechanisms involved in these functions are not fully known. To date, little is known about the possible impact of benznidazole treatment on the T. cruzi-specific functional response of CD4+ T cells. Methodology/Principal findings The functional capacity of CD4+ T cells was analyzed by cytometric assays in chronic Chagas disease patients, with indeterminate form (IND) and cardiac alterations (CCC) (25 and 15, respectively) before and after benznidazole treatment. An increase in the multifunctional capacity (expression of IFN-γ, IL-2, TNF-α, perforin and/or granzyme B) of the antigen-specific CD4+ T cells was observed in indeterminate versus cardiac patients, which was associated with the reduced coexpression of inhibitory receptors (2B4, CD160, CTLA-4, PD-1 and/or TIM-3). The functional profile of these cells shows statistically significant differences between IND and CCC (p<0.001), with a higher proportion of CD4+ T cells coexpressing 2 and 3 molecules in IND (54.4% versus 23.1% and 4.1% versus 2.4%, respectively). A significant decrease in the frequencies of CD4+ T cells that coexpress 2, 3 and 4 inhibitory receptors was observed in IND after 24–48 months of treatment (p<0.05, p<0.01 and p<0.05, respectively), which was associated with an increase in antigen-specific multifunctional activity. The IND group showed, at 9–12 months after treatment, an increase in the CD4+ T cell subset coproducing three molecules, which were mainly granzyme B+, perforin+ and IFN-γ+ (1.4% versus 4.5%). Conclusions/Significance A CD4+ T cell dysfunctional process was detected in chronic Chagas disease patients, being more exacerbated in those patients with cardiac symptoms. After short-term benznidazole treatment (9–12 months), indeterminate patients showed a significant increase in the frequency of multifunctional antigen-specific CD4+ T cells.

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Section: Study Population Materials and Methodsmentioning

confidence: 99%

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

et al. 2021

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“…Female inbred BALB/cAnNCr mice (6–8 weeks old) were purchased from Charles River Laboratories International, Inc. (Wilmington, MA, USA) and housed in specific pathogen-free (SPF) animal facilities at the UBA-PUJ. The BALB/c mouse strain was chosen to minimize variability in comparisons with previous studies (22, 33–35). The animals were housed in ventilated racks in an animal biosafety level 2 (ABSL-2) room under constant noise-free environmental conditions at a room temperature of 21 ± 1°C, a humidity of 50 ± 1%, an air exchange rate of 22.55 air changes/h, and a day–night rhythm of 12–12 h (light phase from 6 a.m. to 6 p.m.) in polycarbonate cages (4 or 5 animals/cage) with sterile soft wood shaving bedding, which was changed weekly.…”

Section: Methodsmentioning

confidence: 99%

An Animal Model of Acute and Chronic Chagas Disease With the Reticulotropic Y Strain of Trypanosoma cruzi That Depicts the Multifunctionality and Dysfunctionality of T Cells

et al. 2019

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Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi , represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20–40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi -infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi -infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi -infected mice. Acute ChD induced a high antigen-specific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes the dysfunctionality of T cells, and these changes might correlate with ChD progression. Thus, these results constitute a model that will facilitate an in-depth search for immune markers and correlates of protection, as well as long-term studies of new immunotherapy strategies for ChD.

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“…Also, the cytokine profile moved toward a more inflammatory environment in infected pregnant women, since the capacity to produce the inflammatory cytokine IFN-γ was less inhibited during pregnancy than the capacity to produce IL-10 (an anti-inflammatory cytokine), being in line with the inflammatory transcriptome detected in the placenta of T. cruzi -infected women [see above (Juiz et al, 2018)]. On the other hand, Egui et al recently observed in a murine experimental T. cruzi infection model that chronic infection reduced the expression of gestation-induced inhibitory receptors on T cells (CTLA4 on CD4 + and CD8 + T cells and CD160 on CD8 + T cells), suggesting that T. cruzi chronic infection counteracts the immunosuppression associated with gestation but does not impact the gestation outcome (Egui et al, 2017).…”

Section: Maternal T Cruzi Systemic Immune Response Gestation and Cmentioning

confidence: 99%

Congenital Transmission of Trypanosoma cruzi: A Review About the Interactions Between the Parasite, the Placenta, the Maternal and the Fetal/Neonatal Immune Responses

et al. 2019

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Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi , is considered a neglected tropical disease by the World Health Organization. Congenital transmission of CD is an increasingly relevant public health problem. It progressively becomes the main transmission route over others and can occur in both endemic and non-endemic countries. Though most congenitally infected newborns are asymptomatic at birth, they display higher frequencies of prematurity, low birth weight, and lower Apgar scores compared to uninfected ones, and some suffer from severe symptoms. If not diagnosed and treated, infected newborns are at risk of developing disabling and life-threatening chronic pathologies later in life. The success or failure of congenital transmission depends on interactions between the parasite, the placenta, the mother, and the fetus. We review and discuss here the current knowledge about these parameters, including parasite virulence factors such as exovesicles, placental tropism, potential placental defense mechanisms, the placental transcriptome of infected women, gene polymorphism, and the maternal and fetal/neonatal immune responses, that might modulate the risk of T. cruzi congenital transmission.

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Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi

Cited by 11 publications

References 36 publications

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

An Animal Model of Acute and Chronic Chagas Disease With the Reticulotropic Y Strain of Trypanosoma cruzi That Depicts the Multifunctionality and Dysfunctionality of T Cells

Congenital Transmission of Trypanosoma cruzi: A Review About the Interactions Between the Parasite, the Placenta, the Maternal and the Fetal/Neonatal Immune Responses

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