Type 1 diabetes (T1D) is an autoimmune disorder characterized by T cell-mediated destruction of pancreatic β cells. Regulatory T cells (Treg) play a pivotal role in maintaining immune homeostasis and suppressing autoimmunity, making them a promising therapeutic strategy for T1D. Current Treg-based therapies include natural Treg (nTreg), TGF-β-induced Treg (iTreg), universal Treg, antigen-specific Treg, and engineered Treg expressing T cell receptors (TCRs) or chimeric antigen receptors (CARs). While nTreg and iTreg have shown efficacy in preclinical models, their clinical application is limited by instability under inflammatory conditions, low numbers, and non-specific immunosuppression. Engineered TCR- and CAR-Treg enable antigen-specific suppression, enhancing targeting, homing to pancreatic islets, and immune-modulatory potency, yet face challenges such as disease-specific antigen identification, Treg stability, exhaustion, and off-target effects. Clinical trials indicate that adoptive Treg therapy is generally safe but often transient in effect, emphasizing the need for early intervention, repeated dosing, or combinatorial strategies (e.g., low-dose IL-2, B cell depletion). Emerging approaches, including integration of chemokine receptor modulation, signal-inducible complexes, and ex vivo engineering to enhance persistence, homing, and suppressive function, hold promise for improving therapeutic outcomes. Future research should focus on optimizing antigen specificity, functional stability, in vivo persistence, and personalized correction of Treg deficiencies to achieve durable immune tolerance. Collectively, advances in TCR and CAR Treg engineering are ushering a new era in Treg-based immunotherapy for T1D, offering potential for safe and effective disease-modifying interventions.
Chen et al. (Mon,) studied this question.