Inhibitory Receptors Are Expressed by Trypanosoma cruzi-Specific Effector T Cells and in Hearts of Subjects with Chronic Chagas Disease

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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CD4+ T cells from chronic Chagas disease patients with different degrees of cardiac compromise exhibit distinct expression patterns of inhibitory receptors TIGIT, Tim-3 and Lag-3

10.1101/694729 ◽

2019 ◽

Author(s):

Paula B. Alcaraz ◽

Magali C. Girard ◽

M. Paula Beati ◽

Raul Chadi ◽

Marisa Fernandez ◽

...

Keyword(s):

T Cells ◽

Chagas Disease ◽

Immune Modulation ◽

Expression Patterns ◽

T Cell Response ◽

Antigenic Stimulation ◽

Inhibitory Receptors ◽

Therapeutic Success ◽

Chronic Chagas Disease

AbstractT cells are central to adaptive immune response against T. cruzi infection. In the chronic stage of Chagas disease, circulating parasite-specific memory T cells show reduced functionality and increased expression of inhibitory receptors, possibly as a result of persistent antigenic stimulation. This exhausted phenotype has been linked to progression of cardiac pathology while, contrariwise, the presence of polyfunctional T cells shows association with therapeutic success and more efficient control of infection. Given this, we hypothesized that inhibitory receptors TIGIT, Tim-3 and Lag-3 may be involved in immune modulation of anti-T. cruzi T cell response, and therefore may play a role in the containment or the unleashing of inflammatory phenomena that ultimately lead to tissue damage and pathology. In this preliminary study, we assess the frequency of CD4+ T cells expressing each of these receptors and their relation to cellular activation. Samples from chronic Chagas disease patients with different degrees of cardiac compromise, and non-infected donors were analyzed under different stimulation conditions. Our results show that the frequency of TIGIT+ CD4+ T cells is increased in Chagas patients, while Tim-3+ cells are more abundant in patients with signs of cardiac alterations. In addition, the frequency of Lag-3+ cells increases in non-activated CD4+ T cells from Chagas patients without demonstrable cardiopathy upon pathogen-specific in vitro antigenic stimulation.

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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

Frontiers in Immunology ◽

10.3389/fimmu.2019.00918 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 8

Author(s):

Jose Mateus ◽

Paula Guerrero ◽

Paola Lasso ◽

Claudia Cuervo ◽

John Mario González ◽

...

Keyword(s):

Animal Model ◽

T Cells ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Chronic Chagas Disease

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Absence of Bim sensitizes mice to experimental Trypanosoma cruzi infection

Cell Death and Disease ◽

10.1038/s41419-021-03964-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Marcela Hernández-Torres ◽

Rogério Silva do Nascimento ◽

Monica Cardozo Rebouças ◽

Alexandra Cassado ◽

Kely Catarine Matteucci ◽

...

Keyword(s):

T Cells ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Parasite Load ◽

Peritoneal Macrophages ◽

T Cell Response ◽

No Production ◽

Similar Reduction ◽

Ifn Γ

AbstractChagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/−, Bim−/− mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim−/− mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/− mice. At the peak of parasitemia, peritoneal macrophages of Bim−/− mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim−/− splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim−/− mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim−/− mice and place Bim as an important protein in the control of T. cruzi infections.

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