美国哈佛医学院Diane Mathis、Chaoran Li小组的最新研究表明产生干扰素-α的浆细胞样树突细胞导致肥胖个体脂肪组织中调节性T细胞(Treg) 的丢失。2021年7月12日，国际学术期刊《细胞-代谢》在线发表了这一成果。

研究人员利用内脏脂肪组织 (VAT)-Treg T细胞受体(TCR)转基因小鼠模型追踪了饮食导致肥胖过程中VAT-Treg亚群的动态和表型变化。结果表明，脂肪代谢相关转录因子PPARγ的下调以及其对促炎细胞因子显著增强的反应共同导致了肥胖小鼠VAT-Tregs细胞的缺失。

特别是，肥胖小鼠（人类也有报道）VAT中高度富集了表达干扰素-α的浆细胞样树突细胞。这些细胞对PPARγ+VAT-Tregs具有直接毒性。通过多种方法阻断肥胖小鼠体内的该通路可显著恢复VAT-Treg亚群并增强胰岛素敏感性。 

据悉，瘦小鼠的内脏脂肪组织具有独特的调节性T细胞 亚群，它们具有独特的转录组和T细胞受体库，并调节局部和全身性炎症及代谢。令人困惑的是，肥胖小鼠并没有这些T细胞亚群，这限制了基于Treg治疗代谢紊乱疗法的应用。

附：英文原文

Title: Interferon-α-producing plasmacytoid dendritic cells drive the loss of adipose tissue regulatory T cells during obesity

Author: Chaoran Li, Gang Wang, Pulavendran Sivasami, Ricardo N. Ramirez, Yanbo Zhang, Christophe Benoist, Diane Mathis

Issue&Volume: 2021-07-12

Abstract: The visceral adipose tissue (VAT) of lean mice hosts a unique population of regulatoryT cells (Tregs) that have a distinct transcriptome and T cell receptor (TCR) repertoireand regulate local and systemic inflammation and metabolism. Perplexingly, this populationdisappears in obese mice, limiting the promise of Treg-based therapies for metabolicdisorders. We exploited the power of a VAT-Treg TCR-transgenic mouse model to followthe dynamics of, and phenotypic changes in, the VAT-Treg population throughout thedevelopment of diet-induced obesity. Our results show that VAT-Tregs are lost underobesogenic conditions due to downregulation of their defining transcription factor,PPARγ, coupled with their strikingly enhanced responses to pro-inflammatory cytokines.In particular, the VAT from obese mice (and reportedly humans) was strongly enrichedin plasmacytoid dendritic cells that actively express interferon-alpha. These cellswere directly toxic to PPARγ+ VAT-Tregs. Blocking this pathway in obese mice by multiple approaches substantiallyrestored the VAT-Treg population and enhanced insulin sensitivity.

DOI: 10.1016/j.cmet.2021.06.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00277-1