Expression of HPGD in regulatory T cells prevents adipose tissue inflammation and metabolic dysfunction (data set 2)

Regulatory T cells (Treg cells) are important for the prevention of autoimmunity and lately, their role in maintaining tissue homeostasis has been demonstrated. They exert their function via different suppressive mechanisms including soluble factors. Here, we show that Treg-cell specific expression of hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into 15-keto PGE2, enforces a new suppressive mode of action through accumulation of the PPAR-gamma ligand 15-keto PGE2. PPAR-gamma-dependent HPGD expression acts as the critical molecular link between prostaglandin metabolism, adipose tissue (AT)-associated Treg-cell function, and maintenance of AT homeostasis. In mice, loss of HPGD results in increased numbers of functionally impaired Treg cells accumulating in visceral adipose tissue resulting in increased local inflammation and systemic insulin resistance. This observation is recapitulated in humans with type 2 diabetes. These data support HPGD as a novel tissue- and context-dependent suppressor mechanism by Treg cells to maintain adipose tissue homeostasis. Isolation of Treg/Tconv cells from VAT of mice with Treg cell specific deletion of Hpgd (n=5) and WT control animals (n=4)调节性T细胞（Regulatory T cells, Treg cells）在预防自身免疫中发挥关键作用，近来其在维持组织稳态中的功能也得到了证实。这类细胞可通过包括可溶性因子在内的多种抑制机制行使功能。本研究证实，羟基前列腺素脱氢酶（hydroxyprostaglandin dehydrogenase, HPGD）的T细胞特异性表达可将前列腺素E2（prostaglandin E2, PGE2）代谢为15-酮基PGE2（15-keto PGE2），并通过积累PPAR-γ配体15-酮基PGE2，确立了一种全新的Treg细胞抑制作用模式。依赖PPAR-γ的HPGD表达是前列腺素代谢、脂肪组织（adipose tissue, AT）相关Treg细胞功能与脂肪组织稳态维持之间的关键分子纽带。在小鼠模型中，HPGD缺失会导致内脏脂肪组织中功能受损的Treg细胞数量增多，进而引发局部炎症加剧与全身性胰岛素抵抗。这一现象在2型糖尿病患者中同样得到了验证。上述研究数据表明，HPGD是Treg细胞介导的、全新的组织与情境依赖性抑制机制，可维持脂肪组织稳态。从Hpgd基因T细胞特异性敲除小鼠（n=5）与野生型对照小鼠（n=4）的内脏脂肪组织（visceral adipose tissue, VAT）中分离Treg细胞与常规T细胞（conventional T cells, Tconv）