1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
1] Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan. [3] Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
Nat Immunol. 2015 Mar;16(3):276-85. doi: 10.1038/ni.3085. Epub 2015 Jan 19.
Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.
叉头框蛋白 3(+) 调节性 T（Treg）细胞存在于内脏脂肪组织（VAT-Treg 细胞）中，是功能特化的组织驻留细胞，可防止肥胖相关炎症，维持胰岛素敏感性和葡萄糖耐量。它们的发育依赖于转录因子过氧化物酶体增殖物激活受体-γ（PPAR-γ）；然而，其分化所需的环境线索尚不清楚。本研究表明，白细胞介素 33（IL-33）通过 IL-33 受体 ST2 和髓样分化因子 MyD88 的信号转导对于 VAT-Treg 细胞的发育和维持至关重要，并维持其转录特征。此外，转录调节因子 BATF 和 IRF4 通过直接调节 ST2 和 PPAR-γ 的表达对于 VAT-Treg 分化是必需的。IL-33 的给药可诱导 VAT-Treg 细胞的大量扩增，这与肥胖小鼠代谢参数的改善密切相关。人类大网膜脂肪组织 Treg 细胞也表现出高 ST2 表达，提示 IL-33 在 VAT-Treg 细胞稳态中具有进化上保守的需求。
