Chagasic cardiomyopathy is marked by a unique signature of activated CD4+ T cells

Almeida, Gregório Guilherme; Rimkutė, Inga; Vale, Isabela Natália Pascoal Campos do; Liechti, Thomas; Henriques, Priscilla Miranda; Roffê, Ester; Araújo, Fernanda Fortes de; Rocha, Manoel Otávio da Costa; Santos, Silvana Maria Elói; Martins‐Filho, Olindo Assis; Janković, Dragana; Sher, Alan; Teixeira-Carvalho, Andréa; Antonelli, Lis Ribeiro do Valle

doi:10.1186/s12967-022-03761-5

Cited by 4 publications

(4 citation statements)

References 55 publications

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Section: Discussionmentioning

confidence: 99%

CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection

Araujo Furlan,

Boccardo,

Rodriguez

et al. 2024

PLoS Pathog

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An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a role during the initial stages after T. cruzi infection, restraining the magnitude of CD8+ T cell responses and parasite control. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation, exhaustion and functional markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell immunity. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, preventing increased parasite replication in T. cruzi infected mice adoptively transferred with Treg cells. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

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Section: Discussionmentioning

confidence: 99%

CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection

Araujo Furlan,

Boccardo,

Rodriguez

et al. 2024

PLoS Pathog

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“…Unsupervised analysis reinforced the heterogeneity of CD4 + T cell subsets and revealed an effector and activated profile of CD4 + T cells in patients with chronic Chagas disease. Previous research has identified that patients with mild chronic Chagas disease exhibit an expansion in activated of CD4 + T cells, and high frequencies of IFN-γ, IFN-γ + TNF + and of IFN-γ + TNF + CD154 + among EM CD4 + T cells compared to CTL ( 48 ). These findings suggest a potential role for these cells in the establishment of cardiac lesions and their potential utility as biomarkers for monitoring disease progression.…”

Section: Discussionmentioning

confidence: 99%

Signatures of CD4+ T and B cells are associated with distinct stages of chronic chagasic cardiomyopathy

Vale,

Almeida,

Rimkute

et al. 2024

Front. Immunol.

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IntroductionChagas disease is a neglected parasitic disease caused by Trypanosoma cruzi. While most patients are asymptomatic, around 30% develop Chronic Chagasic Cardiomyopathy (CCC).MethodsHere, we employed high-dimensional flow cytometry to analyze CD4+ T and B cell compartments in patients during the chronic phase of Chagas disease, presenting the asymptomatic and mild or moderate/severe cardiac clinical forms.ResultsEffector CD27-CD4+ T cells were expanded in both CCC groups, and only mild CCC patients showed higher frequencies of effector memory and T follicular helper (Tfh) cells than healthy donors (CTL) and asymptomatic patients. Unsupervised analysis confirmed these findings and further revealed the expansion of a specific subpopulation composed of Tfh, transitional, and central memory CD4+ T cells bearing a phenotype associated with strong activation, differentiation, and exhaustion in patients with mild but not moderate/severe CCC. In contrast, patients with mild and moderate/severe CCC had lower frequencies of CD4+ T cells expressing lower levels of activation markers, suggesting resting status, than CTL. Regarding the B cell compartment, no alterations were found in naïve CD21-, memory cells expressing IgM or IgD, marginal zone, and plasma cells in patients with Chagas disease. However, expansion of class-switched activated and atypical memory B cells was observed in all clinical forms, and more substantially in mild CCC patients.DiscussionTaken together, our results showed that T. cruzi infection triggers changes in CD4+ T and B cell compartments that are more pronounced in the mild CCC clinical form, suggesting an orchestrated cellular communication during Chagas disease.ConclusionOverall, these findings reinforce the heterogeneity and complexity of the immune response in patients with chronic Chagas disease and may provide new insights into disease pathology and potential markers to guide clinical decisions.

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“…Remarkably, a recent report showed that patients with chronic chagasic cardiomyopathy exhibit expansion of activated effector CD4+ T cell subsets, which correlate with a decreased frequency of CD39+ Treg cells. These data suggest that suppressive mechanisms also operate in the context of the human infection (60). It would be interesting to investigate whether other components of the adenosine pathway are also involved in the control of immune responses in this parasitic infection.…”

Section: Following Activation By Antigen Encounter Cd8+ T Cells Under...mentioning

confidence: 98%

CD39 expression by regulatory T cells drives CD8+ T cell suppression during experimentalTrypanosoma cruziinfection

Araujo Furlan,

Boccardo,

Rodriguez

et al. 2023

Preprint

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An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a critical role during the initial stages after T. cruzi infection, subsequently influencing CD8+ T cells. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell responses. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, leading to improved parasite control during T. cruzi infection. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

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Chagasic cardiomyopathy is marked by a unique signature of activated CD4+ T cells

Cited by 4 publications

References 55 publications

CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection

CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection

Signatures of CD4+ T and B cells are associated with distinct stages of chronic chagasic cardiomyopathy

CD39 expression by regulatory T cells drives CD8+ T cell suppression during experimentalTrypanosoma cruziinfection

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