Organ transplantation remains the cornerstone treatment for end-stage organ failure. While conventional broad-spectrum immunosuppression effectively controls acute rejection, it fails to address chronic rejection and carries long-term side effects including infection, malignancy, and metabolic disorders. Achieving donor-specific immune tolerance while minimizing global immunosuppression has become the central goal of transplant immunology.
Regulatory T cells are recognized as master arbiters of immune homeostasis within the complex transplant immune network. Rather than acting through a single pathway, Tregs employ a coordinated set of precision mechanisms to build a robust defense against graft rejection.
Published in Volume 2, article number 23 of the journal Immunity & Inflammation on April 30, 2026, Professor Xiao-Kang Li's team first summarizes the universal mechanisms by which Tregs function in solid organ transplantation. 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, Tregs establish durable immune tolerance both locally and systemically. This multi-dimensional regulatory toolbox provides the fundamental biological basis for addressing common challenges of rejection across different organs including the liver, kidney, and heart. Understanding these universal principles represent the first step toward precise immune modulation.
How can Tregs be made more controllable, more targeted, and more readily available for large-scale clinical application? The review then systematically traces the technological evolution of Treg therapy from bench to bedside, revealing a paradigm shift from conventional approaches to cutting-edge genetic engineering.
The initial phase involved polyclonal Tregs. Early research focused on expanding autologous Tregs ex vivo. While safety was established, this approach faced limitations including insufficient specificity and challenges in expansion efficiency. The next phase brought CAR-Tregs (chimeric antigen receptor-engineered Tregs). The introduction of CAR technology equipped Tregs with a "navigation system," enabling them to precisely recognize graft antigens and exert potent local immunosuppressive effects.
The most recent revolutionary breakthrough involves "off-the-shelf" universal products. The field is now at a critical stage where gene-editing technologies such as CRISPR-Cas9 are being used to create hypoimmunogenic Tregs. By knocking out human leukocyte antigen molecules, these engineered Tregs can evade the recipient's immune system, enabling standardized, scalable "off-the-shelf" availability. This stepwise technological evolution is driving transplant medicine away from a highly personalized and complex surgical procedure toward standardized, accessible cell drug therapy.
"Future breakthroughs in transplant immunology depend on integrating universal technology platforms (such as universal CAR-Tregs) with a deep understanding of organ-specific immune microenvironments," the authors point out. By combining the targeting capability of CARs, the convenience of off-the-shelf products, and the power of synergistic immune regulation, Treg therapy will become a precisely tailored translational medicine strategy designed to provide durable, stable immune tolerance for patients across the full 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 basic mechanisms, organ-specific microenvironment differences, technological iterations, and clinical translation, it provides both theoretical support and practical pathways for improving long-term outcomes in solid organ transplantation. "As gene editing, cell engineering, and precision immune regulation technologies become increasingly integrated, Treg cell therapy is poised to become a landmark breakthrough in transplant medicine, ultimately realizing the ideal state of low or zero immunosuppressant dependency," the authors look ahead.
