Regulatory T cells (Tregs) are a cornerstone of immunology, indispensable for maintaining immune homeostasis and preventing autoimmune reactions. Since their identification and characterization through pioneering studies by Prof. Shimon Sakaguchi and other leading researchers, Tregs have revolutionized our understanding of the immune system’s checks and balances. Recent research has elucidated diverse molecular and cellular pathways by which Tregs enforce immune tolerance, uncovered their interactions within specific tissue microenvironments, and mapped their roles in diverse contexts such as autoimmunity, transplantation, and allergy. Notwithstanding these advances, significant challenges remain in translating basic Treg biology into clinical interventions—particularly in stabilizing their function, harnessing their specificity, and overcoming barriers in hostile or inflamed tissues. Ongoing debates explore the optimal manipulation of Tregs for therapy, the mechanisms governing their stability and plasticity, and the complex interplay with other immunoregulatory pathways.

This Research Topic aims to consolidate and advance knowledge on Tregs as both critical mediators of immune regulation and as promising therapeutic agents. The central objectives are to deepen mechanistic insights into how Tregs establish and sustain tolerance, explore innovative technologies such as chimeric antigen receptor Tregs (CAR-Tregs), and investigate new strategies for harnessing these cells in clinical settings. Contributions are encouraged to address unresolved questions, such as how Tregs may be manipulated to achieve durable tolerance in challenging diseases, how novel epitopes shape their expansion and function, and how technological advances can surmount current translational obstacles. A special emphasis will also be placed on the integration of pioneering findings presented at recent symposia, with the objective of charting actionable pathways from discovery to application.

The scope of this Research Topic encompasses foundational and translational aspects of Treg biology, focusing on pathways and approaches that underpin, enhance, or exploit tolerance mechanisms. While the principal emphasis lies in immune regulation in human health and disease, contributions exploring broader applications and cross-disciplinary methodologies are also welcomed. To gather further insights in these dynamic areas, we welcome articles addressing, but not limited to, the following themes:

-Molecular and cellular mechanisms driving Treg-mediated tolerance
-Strategies for stabilizing and expanding Tregs for adoptive cell therapy
-Advances in chimeric antigen receptor Tregs (CAR-Tregs) and targeted applications
-Discovery and characterization of Tregitopes, microbial, or helminth-derived Treg activators
-The role of Tregs in shaping tissue microenvironments and modulating co-inhibitory pathways
-Clinical challenges and breakthroughs in Treg-based therapies for autoimmunity, transplantation, allergy, and inflammation
-Manipulation of FOXP3 and other molecular regulators essential for Treg identity and function
-Integration of adenosinergic and immune checkpoint pathways in Treg biology

Annie S De Groot is the principal owner of Epivax, Inc. All other topic editors declare no Conflict of Interest

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Tregs as medicine: Translational advances and clinical frontiers