Regulatory T cells in autoimmune diseases: biological mechanisms, clinical translation, and translational challenges

Autoimmune diseases (ADs) are a group of inflammatory disorders triggered by aberrant immune responses against autoantigens and the breakdown of immune tolerance. Current therapeutic strategies, such as glucocorticoids and immunosuppressants, exert largely non-specific immunomodulation and are frequently associated with substantial adverse effects upon long-term administration. As such, these approaches are often insufficient to re-establish immune homeostasis. In recent years, regulatory T cell (Treg)-based therapeutics have undergone rapid advancement, with continuously updated therapeutic modalities broadening the application boundary of immune tolerance intervention. This review comprehensively outlines the progress of Treg-based therapeutics, spanning from fundamental biological research to translational applications in autoimmune diseases. We describe the developmental characteristics, suppressive machinery, and heterogeneity of Tregs, and highlight the preclinical and clinical advancements of diverse Treg therapeutic modalities, including polyclonal and antigen-specific Tregs, TCR-engineered Tregs, and CAR-Tregs. Furthermore, we emphasize current optimization strategies for enhancing Treg stability, antigen specificity, and in vivo fitness within inflammatory microenvironments. Additionally, we objectively address the major translational bottlenecks of Treg therapy and provide future perspectives to facilitate the clinical implementation of Treg-based immunotherapies for autoimmune diseases.