Semin Immunol. 2026 May 15;82:102030. doi: 10.1016/j.smim.2026.102030. Online ahead of print.
ABSTRACT
Chagas disease, caused by Trypanosoma cruzi, remains one of the most striking examples of how parasite genetic diversity and host immune heterogeneity converge to shape chronic infection outcomes. This review integrates findings from studies across Latin America -Mexico and Central America, the Andean countries, Brazil, and Argentina – to reveal both shared and region-specific features of T-cell response and cytokine immune regulation in chronic infection. Across regions, disease progression reflects the balance between proinflammatory and regulatory networks: effective parasite control depends on IFN-γ- and TNF-α-driven Th1 and cytotoxic responses, yet persistent activation and insufficient counter-regulation by IL-10, TGF-β, and regulatory lymphocytes lead to immune dysregulation, inflammation, and fibrosis. IND patients maintain polyfunctional and IL-10-modulated T-cell responses, whereas patients with cardiomyopathy display monofunctional, exhausted effector cells expressing inhibitory receptors such as PD-1, CTLA-4, and TIM-3. Distinct cytokine profiles and immune-checkpoint dynamics observed among populations likely reflect differences in host genetics, immune background, and parasite diversity across the continent. Together, these findings outline a continuum of immune regulation in human Chagas disease and emphasize that restoring the equilibrium between effector and regulatory pathways – rather than amplifying one over the other – will be key for developing future immunomodulatory therapies and vaccines. Further understanding how parasite lineage, host genetics, and environmental context shape T-cell and cytokine networks is essential to develop regionally tailored immunotherapies and vaccines capable of restoring immune homeostasis without exacerbating pathology and, importantly, instruct strategies that can be used in all regions.
PMID:42140003 | DOI:10.1016/j.smim.2026.102030