Precision Immunoregulation in transplantation: The rise of engineered Treg therapies.

Regulatory T cells (Tregs) are key mediators of immune tolerance and play a critical role in limiting excessive immune activation in conditions such as autoimmunity, transplantation, and graft-versus-host disease. Tregs are broadly classified into thymic-derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which differ in lineage stability, epigenetic regulation, and functional plasticity. The suppressive function of tTregs is supported by stable expression of the transcription factor FOXP3, reinforced by demethylation of the Treg-specific demethylated region (TSDR). In contrast, pTregs are more susceptible to inflammatory cytokine signaling, which can destabilize FOXP3 expression and compromise suppressive function. Tregs employ multiple mechanisms of immune regulation, including CTLA-4-mediated inhibition of co-stimulatory signaling, cytokine modulation, metabolic interference, and, in certain contexts, granzyme-dependent cytotoxicity. Advances in cellular engineering have enabled the development of next-generation Treg therapies, including ex vivo expanded polyclonal Tregs, antigen-specific Tregs, and chimeric antigen receptor (CAR)-modified Tregs. Early-stage clinical and preclinical studies indicate that these approaches are feasible and exhibit favorable safety profiles in transplantation and immune-mediated diseases. This review summarizes current understanding of Treg biology, mechanisms governing lineage stability, and emerging strategies to enhance Treg specificity, persistence, and suppressive capacity, while highlighting remaining translational challenges.