Pompura Saige L, Wagner Allon, Kitz Alexandra, LaPerche Jacob, Yosef Nir, Dominguez-Villar Margarita, Hafler David A
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Electrical Engineering and Computer Science, and the Center for Computational Biology, University of California Berkeley, Berkeley, California, USA.
J Clin Invest. 2021 Jan 19;131(2). doi: 10.1172/JCI138519.
FOXP3+ Tregs rely on fatty acid β-oxidation-driven (FAO-driven) oxidative phosphorylation (OXPHOS) for differentiation and function. Recent data demonstrate a role for Tregs in the maintenance of tissue homeostasis, with tissue-resident Tregs possessing tissue-specific transcriptomes. However, specific signals that establish tissue-resident Treg programs remain largely unknown. Tregs metabolically rely on FAO, and considering the lipid-rich environments of tissues, we hypothesized that environmental lipids drive Treg homeostasis. First, using human adipose tissue to model tissue residency, we identified oleic acid as the most prevalent free fatty acid. Mechanistically, oleic acid amplified Treg FAO-driven OXPHOS metabolism, creating a positive feedback mechanism that increased the expression of FOXP3 and phosphorylation of STAT5, which enhanced Treg-suppressive function. Comparing the transcriptomic program induced by oleic acid with proinflammatory arachidonic acid, we found that Tregs sorted from peripheral blood and adipose tissue of healthy donors transcriptomically resembled the Tregs treated in vitro with oleic acid, whereas Tregs from patients with multiple sclerosis (MS) more closely resembled an arachidonic acid transcriptomic profile. Finally, we found that oleic acid concentrations were reduced in patients with MS and that exposure of MS Tregs to oleic acid restored defects in their suppressive function. These data demonstrate the importance of fatty acids in regulating tissue inflammatory signals.
FOXP3+调节性T细胞（Tregs）的分化和功能依赖于脂肪酸β-氧化驱动（FAO驱动）的氧化磷酸化（OXPHOS）。最近的数据表明Tregs在维持组织稳态中发挥作用，组织驻留Tregs具有组织特异性转录组。然而，建立组织驻留Treg程序的特定信号在很大程度上仍然未知。Tregs在代谢上依赖于FAO，考虑到组织中富含脂质的环境，我们推测环境脂质驱动Treg稳态。首先，利用人类脂肪组织模拟组织驻留，我们确定油酸是最普遍的游离脂肪酸。从机制上讲，油酸增强了Treg的FAO驱动的OXPHOS代谢，形成了一种正反馈机制，增加了FOXP3的表达和STAT5的磷酸化，从而增强了Treg的抑制功能。将油酸诱导的转录组程序与促炎花生四烯酸诱导的程序进行比较，我们发现从健康供体的外周血和脂肪组织中分离出的Tregs在转录组上类似于体外经油酸处理的Tregs，而来自多发性硬化症（MS）患者的Tregs更类似于花生四烯酸转录组图谱。最后，我们发现MS患者的油酸浓度降低，并且将MS Tregs暴露于油酸可恢复其抑制功能缺陷。这些数据证明了脂肪酸在调节组织炎症信号中的重要性。
