Immunological exhaustion and functional profile of CD8+ T lymphocytes as cellular biomarkers of therapeutic efficacy in chronic Chagas disease patients

Pérez-Antón, Elena; Egui, Adriana; Thomas, María del Carmen; Simón, Marina; Segovia, Manuel; López, Manuel Carlos López

doi:10.1016/j.actatropica.2019.105242

Cited by 14 publications

(11 citation statements)

References 40 publications

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“…T‐cell exhaustion is a feature of many infectious and non‐infectious diseases that involve chronic antigen stimulation and this has been a recent focus of research in the Chagas disease field. Analysis of PBMCs from Chagas patients revealed increased frequencies of CD4 + and CD8 + T cells expressing exhaustion markers, for example PD‐1 + , CTLA4 + , or TIM‐3 + 193‐195 . Experimental studies suggest the development of exhaustion characteristics may be promoted by suboptimal B cell, 152 IL‐17A 196 or IL‐10 156 immune responses.…”

Section: Stage 3: the 1% And The Chronic Host‐parasite Equilibriummentioning

confidence: 99%

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Pérez‐Mazliah

Ward

Lewis

2020

Parasite Immunology

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Trypanosoma cruzi is a remarkably versatile parasite. It can parasitize almost any nucleated cell type and naturally infects hundreds of mammal species across much of the Americas. In humans, it is the cause of Chagas disease, a set of mainly chronic conditions predominantly affecting the heart and gastrointestinal tract, which can progress to become life threatening. Yet around two thirds of infected people are long‐term asymptomatic carriers. Clinical outcomes depend on many factors, but the central determinant is the nature of the host‐parasite interactions that play out over the years of chronic infection in diverse tissue environments. In this review, we aim to integrate recent developments in the understanding of the spatial and temporal dynamics of T. cruzi infections with established and emerging concepts in host immune responses in the corresponding phases and tissues.

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Section: Stage 3: the 1% And The Chronic Host‐parasite Equilibriummentioning

confidence: 99%

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Pérez‐Mazliah

Ward

Lewis

2020

Parasite Immunology

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“…Although a cause-effect link between T-cell exhaustion and disease progression cannot be ascertained, they are likely to be interconnected. Adult subjects, even in the G0 group, displayed signs of T-cell exhaustion, including lower frequency and magnitude of polyfunctional T cells compared with T. cruzi-infected children [7], expression of inhibitory receptors on T. cruzi-specific T cells [14,64] and total T cells [8,9], and high levels of terminal, differentiated, and apoptotic T cells [65]; all of which worsen in more severe clinical stages. CD4 + T cell responses improved after in vitro treatment with IL-27 and IL-7 only in subjects without signs of heart disease who have a more functional IL-27 and IL-7 axis and less exhausted immune system compared with those in patients with severe cardiomyopathy.…”

Section: Fig 7 Bcl-2 Expression Is Higher In Ifn-γ-and Il-2-coproducimentioning

confidence: 99%

“…cruzi -infected children, who are presumed to have shorter-term infections compared with adults, showed a higher proportion of polyfunctional CD4 + T cells responsive to T . cruzi antigens in their circulation [ 7 ] relative to chronic infected adults [ 7 – 9 ]. The impairment of T .…”

Section: Introductionmentioning

confidence: 99%

“…T helper 1 (Th1) and T cytotoxic (Tc) cells are critical for T. cruzi immunity [5] and are impaired over time [6,7]. T. cruzi-infected children, who are presumed to have shorter-term infections compared with adults, showed a higher proportion of polyfunctional CD4 + T cells responsive to T. cruzi antigens in their circulation [7] relative to chronic infected adults [7][8][9]. The impairment of T. cruzi-specific T-cell function is more pronounced in patients with advanced cardiomyopathy [6,8,10].…”

Section: Introductionmentioning

confidence: 99%

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Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro

et al. 2021

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In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes TBX21, EOMES and CXCL9 in response to IL-27. In vitro treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected.

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“…In terms of T cell immune responses, it has been recently described that Chagas patients with cardiac tissue damage present higher expression levels of T-cell inhibitory receptors and lower antigen-specific capacity compared with that of asymptomatic patients (60). These features were partially reversed by BNZ treatment in both asymptomatic and symptomatic patients: the co-expression of inhibitory molecules was reduced, the multifunctional antigen-specific response of CD8 + T cells was enhanced, and an increase in the subset of cells with cytotoxic proprieties and production of IFN-γ was observed.…”

Section: Markers Associated With the Host Immune Statementioning

confidence: 99%

State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response

Cortes-Serra

Losada

Pinazo

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Chagas disease is caused by infection with the parasite Trypanosoma cruzi, which might lead to a chronic disease state and drive to irreversible damage to the heart and/or digestive tract tissues. Endemic in 21 countries in the Americas, it is the neglected disease with a highest burden in the region. Current estimates point at ~6 million people infected, of which ~30% will progress onto the symptomatic tissue disruptive stage. There is no vaccine but there are two anti-parasitic drugs available: benznidazole and nifurtimox. However, their efficacy is variable at the chronic symptomatic stage and both have frequent adverse effects.Since there are no prognosis markers, drugs should be administered to all T. cruzi-infected individuals in the indeterminate and early symptomatic stages. Nowadays, there are no testsof-cure either, which greatly undermines patients´ follow-up and the search of safer and more efficacious drugs. Therefore, the identification and validation of biomarkers of disease progression and/or treatment response on which to develop tests of prognosis and/or cure is a major research priority. Both parasite-and host-derived markers have been investigated. In the present manuscript we present an updated outlook of the latter.

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Immunological exhaustion and functional profile of CD8+ T lymphocytes as cellular biomarkers of therapeutic efficacy in chronic Chagas disease patients

Cited by 14 publications

References 40 publications

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro

State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response

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