Zhihui Zhang, Yongtao Li, Huan Li, Mi Zhang, Zhen Qian, Baiyi Li, Nu Chen, Jiawei Wang, Xuexue Cui, Mengjuan Zhang, Song Zhang, Lai Wei, Xiaomin Zhang
T cell–mediated autoimmune diseases remain difficult to manage owing to limited options and adverse effects of current immunosuppressants; safer, tolerance-preserving approaches are needed. We identify pigment epithelium-derived factor (PEDF) as an endogenous regulator of ocular immunity with therapeutic potential. PEDF expression was induced during autoimmune uveitis (AU) in patients and during experimental autoimmune uveitis (EAU) progression, suggesting an endogenous compensatory response to inflammatory stress. Loss of PEDF did not substantially alter early peripheral immune activation but impaired inflammatory control during established disease, leading to persistent retinal inflammation and reduced Foxp3⁺ regulatory T (Treg) responses. Conversely, intravitreal administration of recombinant PEDF enhanced Treg responses and promoted inflammatory resolution, thereby alleviating EAU severity. Mechanistically, we delineate a PEDF–ATGL–DHA–PPARγ axis that reprograms Treg metabolism: PEDF activates adipose triglyceride lipase (ATGL) to mobilize docosahexaenoic acid (DHA), enhancing mitochondrial oxidative metabolism and stabilizing Foxp3 via PPARγ. Together, these findings establish PEDF as a physiological checkpoint that links lipid utilization to immune tolerance, and demonstrate a metabolism-centered, cytokine-independent strategy to reinforce Treg stability in vivo. Having shown efficacy in an ocular model of T cell–driven autoimmunity, PEDF-based immunometabolic modulation defines a broadly applicable strategy for restoring immune tolerance across T cell–mediated autoimmune diseases.