Expression of HPGD in regulatory T cells prevents adipose tissue inflammation and metabolic dysfunction (data set 1)

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-? ligand 15-keto PGE2. PPAR-?-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. Overall design: Isolation of WT (n=4) and Hpgd-deficient (n=3) Treg cells from mLN of Rag-/- mice 8 weeks after injection with WT naive T cells, WT Treg cells and either YFP+ WT or YFP+ Hpgd-deficient Treg cells