Regulatory T cell therapy and immune tolerance in heart transplantation: a translational evidence framework for regulatory T cells-cell characterization and recipient-graft monitoring

Regulatory T cell (Treg) therapy is a candidate strategy for improving donor-specific immune regulation after heart transplantation and, in the long term, may reduce reliance on lifelong immunosuppression. This Review separates mechanistic and preclinical evidence from human case observations, prospective clinical-trial protocols, manufacturing studies, and translational hypotheses. We summarize pathways that support Treg function in experimental transplantation and evaluate context-dependent outputs, including amphiregulin and CXCL15-related signaling, as potential safety signals rather than validated clinical biomarkers. We then compare peripheral-blood-derived and thymus-derived Treg-cell preparations, focusing on source material, manufacturing, cryopreservation, cell identity and potency, and infusion timing. Human evidence for Thy-Tregs in heart transplantation includes one fully reported index case and preliminary, incompletely reported data on the first four THYTECH recipients. ATT-Heart provides a prospective phase I evaluation framework. Finally, we assess allogeneic Thy-Treg banks, thymic organoids, and thymic transplantation as exploratory routes for adult recipients. The central translational question is whether a defined Treg-cell therapy can persist, remain functionally stable, and be monitored safely in the inflammatory environment of cardiac transplantation.