Estudo da expressão gênica e de características funcionais das células T gama-delta na doença de Chagas humana

Abstract

Chagas disease (ChD) is a parasitic illness caused by the intracellular protozoan Trypanosoma cruzi, first identified in 1909 by the Brazilian physician Carlos Chagas. It is classified as a neglected tropical disease. Chronic Chagas cardiomyopathy (CCC) represents the most severe consequence of the chronic phase of ChD and is one of the deadliest known human cardiomyopathies. Despite being described over a century ago, no vaccines are currently available to prevent CCC, and treatment is limited to two drugs with suboptimal efficacy and significant side effects. The mechanisms underlying the development and progression of CCC are not fully understood. T lymphocytes expressing the gamma-delta T cell receptor (TCR γδ) constitute a minor yet highly active population in human peripheral blood. These cells are present in the blood of CCC patients, and TCR γδ–related transcripts, but not TCR αβ–related transcripts, are upregulated in their cardiac tissue. In this study, we investigated the transcriptomic, phenotypic, and functional profiles of circulating γδ T cells in patients with CCC compared with those with the indeterminate form (IND) of Chagas disease, who do not present with cardiomyopathy. Through single-cell RNA sequencing (scRNA-seq) using a panel of 400 immune-related genes, we identified a pronounced cytotoxic and pro-inflammatory potential in double-negative (DN) and CD8⁺ γδ T cells from CCC patients compared with IND patients. Using multiparametric flow cytometry, we confirmed these transcriptional findings by demonstrating functional heterogeneity in the γδ T cell compartment between IND and CCC groups. While CD4⁺ and CD4⁻CD8⁻ (double-negative, DN) γδ T cells from CCC patients were biased toward cytokine production and exhibited a pro-inflammatory profile, CD8⁺ γδ T cells showed high expression of the TNF-α receptor, suggesting increased responsiveness to the prevailing inflammatory milieu. Circulating CD8⁺ γδ T cells from CCC patients expressed cardiotropic inflammatory chemokine receptors, indicating possible cardiac migration, along with cytotoxic molecules that positively correlated with cardiac dysfunction. Finally, we demonstrated the potential use of pentoxifylline as a promising therapeutic candidate capable of dampening the inflammatory profile of γδ T cells, offering new perspectives for managing CCC and other inflammatory cardiomyopathies involving these cells.