Regulatory T cell dysfunction and exhaustion in uveitis: immunometabolic mechanisms, microenvironmental drivers, and emerging therapeutic strategies

Non-infectious uveitis encompasses a diverse array of autoimmune ocular disorders marked by the breakdown of immune tolerance and recurrent inflammatory episodes. Regulatory T cells (Tregs) are integral to the maintenance of ocular homeostasis in all subtypes of this condition. However, Behçet’s disease, Vogt-Koyanagi-Harada (VKH) disease, and HLA-B27-associated uveitis exhibit distinct patterns of Treg quantitative reduction, lineage instability, and functional exhaustion. Tregs play a crucial role in maintaining ocular homeostasis; however, their quantitative reduction, lineage instability, and functional exhaustion significantly contribute to the persistence of the disease. This review provides a systematic synthesis of the molecular and immunometabolic mechanisms underlying Treg exhaustion in uveitis, emphasizing both universal pathways and subtype-specific mechanisms. We examine critical intrinsic regulators of Treg fitness, including the multidimensional control of FoxP3 stability, the upregulation of inhibitory checkpoints such as TIGIT and PD-1, and the dysregulated plasticity within the Th17/Treg axis. Additionally, the review emphasizes how extrinsic microenvironmental factors influence Treg functionality, with a specific focus on adenosine A2A receptor (A2Ar) signaling, circadian rhythm disruption mediated by the clock gene Per1, and the immunomodulatory role of gut microbiota. Regarding therapeutic strategies, we evaluate recent advances in restoring Treg competence, including immune checkpoint agonists, metabolic reprogramming agents (e.g., Itaconate), and traditional herbal formulations.