Regulatory T cells in homeostasis and disease: molecular mechanisms and therapeutic potential

Abstract Regulatory T cells (Treg cells or Tregs), a subset of CD4⁺ T cells with immunosuppressive properties, are essential for immune homeostasis and self-tolerance. Characterized by their immunosuppressive capabilities and reliance on the transcription factor Foxp3 (Forkhead box protein P3), Tregs employ multiple mechanisms, including cytokine secretion, metabolic control, and cell contact inhibition, to restrain excessive immune activation to prevent autoimmunity while maintaining tissue repair processes. However, dysregulation in their frequency or function—whether deficiency or hyperactivity—is implicated in diverse pathologies, spanning autoimmune disorders, cancer progression, transplant rejection, and emerging associations with neurological and cardiovascular diseases. Thus, Treg-targeted strategies represent a promising approach for restoring immune balance under various conditions. This review synthesizes current knowledge on Treg biology, from their discovery and definition of markers to their new regulatory mechanisms. We further explore the roles of Tregs across diseases, emphasizing their context-dependent therapeutic potential. Strategies to deplete or inhibit Tregs in cancer immunotherapy contrast with approaches to expand or stabilize their function in autoimmunity and transplantation. However, challenges persist, including achieving tissue-specific targeting, ensuring the functional stability of engineered Tregs, and minimizing off-target effects. By integrating mechanistic insights with translational innovations, this review provides a roadmap for advancing Treg-based therapies, ultimately aiming to restore immune equilibrium in a disease-specific manner.