Abstract
Regulatory T cells (Tregs) are indispensable for maintaining immune homeostasis and suppressing excessive inflammatory responses in the intestine. While much attention has focused on positive regulators of Treg differentiation and function, the mechanisms that constrain Treg transcriptional and metabolic programs remain poorly understood. Here, miR-10a is identified as a key negative regulator of Treg suppressive capacity and their crosstalk with intestinal epithelial cells. Single-cell and bulk transcriptomic analyses reveal that Treg-specific deletion of miR-10a promotes an effector Treg (eTreg) phenotype characterized by elevated Blimp1 expression, a direct target of miR-10a. MiR-10a-deficient Tregs demonstrate enhanced suppressive capacity in alleviating colitis without compromising Treg stability. Mechanistically, miR-10a deficiency drives metabolic reprogramming, highlighted by altered mitochondrial oxidative phosphorylation through Uqcrq, a component of mitochondrial complex III. Loss of Uqcrq impairs Treg suppressive function in colitis but does not affect stability. Furthermore, miR-10a targets amphiregulin (Areg), an epidermal growth factor-like molecule crucial for mucosal epithelial repair. Areg-deficient Tregs exhibit decreased intestinal barrier function, whereas miR-10a-deficient Tregs exhibit enhanced barrier function in experimental colitis. These findings define a multifaceted role for intrinsic miR-10a in negatively regulating Treg function by integrating transcriptional, metabolic, and epithelial repair pathways, thereby unveiling potential therapeutic interventions in inflammatory bowel diseases.