Abstract
Purpose :
Regulatory T cells (Tregs) play a crucial role in the pathological mechanisms of Uveitis. The oxidative phosphorylation driven by mitochondrial lipid metabolism plays a critical role in Treg fate. Pigment epithelium-derived factor (PEDF) has been identified as a regulator of mitochondrial fatty acid metabolism and angiogenesis. However, the impact of PEDF on the mitochondrial metabolic programs of Tregs and its relevance to uveitis remains unclear. This study aimed to investigate the influence of PEDF on the metabolic program and immunosuppressive function of Tregs both in vivo and in vitro.
Methods :
Vogt–Koyanagi–Harada disease (VKH) patient samples and Experimental autoimmune uveitis (EAU) mice were employed to assess PEDF expression during the autoimmune response. PEDF knockout (KO) mice were utilized to explore the effects of PEDF on the pathogenesis of EAU, as well as Treg cell differentiation and immunosuppressive function. The Seahorse assay was applied to evaluate the impact of PEDF on mitochondrial basal metabolic rate. RNA-seq analysis and Metabolomics were conducted to elucidate the molecular mechanism of PEDF in regulating Treg cell fate.
Results :
We observed high PEDF expression in uveitis patients and during the development of EAU. Additionally, in vitro experiments revealed that TCR-activated CD4+ T cells, especially Tregs, are the primary producers of PEDF. PEDF knockout (KO) exacerbates EAU symptoms by enhancing pathogenic Th17 cells and diminishing Tregs both locally in the eye and within the peripheral immune system (Fig 1). PEDF KO hampers the differentiation and immunosuppressive capabilities of Tregs, leading to reduced IL-10 expression. PEDF KO influences Tregs responses by diminishing mitochondrial oxidative phosphorylation (OXPHOS) and disrupting lipid metabolism (Fig 2).
Conclusions :
PEDF acts as a critical metabolic regulator that fine-tunes Tregs differentiation and function in autoimmune uveitis.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.