Dynamics and functional heterogeneity of FOXP3+ regulatory T cells in Trypanosoma cruzi infection: a systematic review.

BACKGROUND

The role of regulatory T cells (Tregs) in Trypanosoma cruzi infection remains unresolved, with conflicting evidence suggesting either protection from immunopathology or impairment of parasite control.

METHODS

We performed the first systematic review integrating data on Treg phenotype and function in human and experimental Chagas disease. A comprehensive search of PubMed, Embase, Scopus, and LILACS (2003-2025) identified studies assessing Tregs during T. cruzi infection. Study selection, data extraction, and risk-of-bias assessment followed PRISMA 2020 and Cochrane guidelines.

RESULTS

Twenty-seven studies met eligibility criteria (9 human, 18 murine). Human studies consistently showed that individuals with indeterminate Chagas disease harbor functionally stable Tregs enriched for CD39, CD25high, and CTLA-4 expression. In contrast, Chagas cardiomyopathy was associated with Treg instability, PD-1 upregulation, and partial acquisition of Th1-like features. Murine models revealed a phase-dependent role: transient Treg restriction during acute infection enhanced CD8⁺ T cell-mediated parasite control, whereas failure to re-establish regulatory balance promoted chronic cardiac inflammation. Key modulatory pathways included IL-10, IL-2, IL-33/ST2, G-CSF, and CD39.

CONCLUSION

These findings support a dual-role model in which Tregs dynamically coordinate disease tolerance. Treg-associated signatures, particularly CD39 expression and activated/resting Treg ratios, emerge as promising biomarkers and therapeutic targets for Chagas disease.