Organ transplantation remains the basic treatment for end-stage organ failure. Although conventional broad-spectrum immunosuppression effectively controls acute rejection, it cannot address chronic rejection and is associated with long-term side effects such as infections, malignancies, and metabolic disorders. Achieving donor-specific immune tolerance while minimizing global immunosuppression has become a central goal of transplant immunology.
Regulatory T cells are recognized as master arbiters of immune homeostasis within complex transplanted immune networks. Rather than acting through a single pathway, Tregs use a coordinated set of precise mechanisms to build a robust defense against graft rejection.
Published in magazine volume 2, article number 23 immunity and inflammation On April 30, 2026, Professor Xiao-Kang Li’s team summarized for the first time the universal mechanism by which Tregs function in solid organ transplantation. Tregs establish durable immune tolerance locally and systemically through the secretion of inhibitory cytokines (such as IL-10 and TGF-β), induction of effector T cell apoptosis, and modulation of dendritic cell function. This multidimensional regulatory toolbox provides a fundamental biological basis for addressing the common challenges of rejection across various organs such as the liver, kidneys, and heart. Understanding these universal principles is the first step toward precise immune regulation.
How can Tregs be made more controllable, targeted, and readily available for large-scale clinical applications? This review then systematically tracks the technological evolution of Treg therapy from bench to bedside, highlighting the paradigm shift from traditional approaches to cutting-edge genetic engineering.
Early stages included polyclonal Tregs. Early studies focused on the expansion of autologous Tregs in vitro. While this approach has established safety, it has faced limitations such as insufficient specificity and scaling efficiency challenges. In the next step, CAR-Tregs (chimeric antigen receptor-modified Tregs) were introduced. With the introduction of CAR technology, Tregs are now equipped with a “navigation system” that allows them to accurately recognize graft antigens and exert strong local immunosuppressive effects.
The latest revolutionary advances include “off-the-shelf” general-purpose products. The field is currently at an important stage in using gene editing technologies such as CRISPR-Cas9 to create less immunogenic Tregs. By knocking out human leukocyte antigen molecules, these genetically engineered Tregs evade the recipient’s immune system, allowing for standardized, scalable, “off-the-shelf” availability. This gradual technological evolution is moving transplant medicine from highly individualized and complex surgical procedures to standardized and easily accessible cellular drug therapies.
”Future advances in transplant immunology will depend on a deep understanding of organ-specific immune microenvironments and the integration of universal technology platforms (such as universal CAR-Tregs).‘, the authors point out. By combining the targeting capabilities of CARs, the convenience of off-the-shelf products, and the power of synergistic immune regulation, Treg therapy will become a precisely customized translational medical strategy designed to provide patients with durable and stable immune tolerance across the entire spectrum of solid organ transplantation, opening a new era of “immunosuppression-free” transplantation.
This comprehensive review maps the complete paradigm shift from passive immunosuppression to active tolerance induction. By integrating fundamental mechanisms, organ-specific microenvironment differences, technique iterations, and clinical applications, we provide both theoretical support and practical pathways to improve long-term outcomes in solid organ transplantation. ”With the increasing integration of gene editing, cell engineering, and precision immune regulation techniques, Treg cell therapy is poised to become a major breakthrough in transplant medicine, ultimately achieving the ideal state of low or no dependence on immunosuppressants.“The author is looking ahead.
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Reference magazines:
Lee, S.W.; Others. (2026) From immunosuppression to active tolerance induction: an evolving paradigm for regulatory T cell-based therapy in organ transplantation. immunity and inflammation. DOI: 10.1007/s44466-026-00037-1. https://link.springer.com/article/10.1007/s44466-026-00037-1
