Regulatory T cells (Treg cells) are essential for maintaining immune homeostasis. However, how Treg cells exert their function in tissue specific environments is often unknown. We have found hydroxyprostaglandin dehydrogenase (Hpgd), the major Prostaglandin E2 (PGE2) metabolizing enzyme, to be significantly upregulated in Treg cells compared to conventional T cells (Tconv). In the murine system, this upregulation is especially pronounced in the visceral adipose tissue (VAT), a prostaglandin-rich environment. Furthermore, we could show that through the metabolism of PGE2 into 15-keto-PGE2 Hpgd enhances the suppressive capabilities of Treg cells in an, at least partially, Pparγ-dependent manner. In vivo, we found that Hpgd-deficient Treg cells were less efficient in preventing the onset of both DSS-induced and adoptive transfer colitis, further indicating that Hpgd plays a role in the suppressive capacity of Treg cells. However, analysis of the transcriptome of these Hpgd-deficient Treg cells did not differ significantly from Hpgd-competent Treg cells, indicating that the observed changes are due to the extrinsic effect caused by the loss of the enzymatic function of Hpgd. When analyzing the VAT of aged animals with Hpgd-deficient Treg cells, we could detect an influx of non-functional Treg cells as well as an accumulation of pro-inflammatory macrophages and an increase in adipocyte size. Furthermore, while we could neither detect a change in body or organ weight of these animals, nor a change in motility, food and water intake, or respiration, we could observe impaired metabolic signaling. Aged animals with Hpgd-deficient Treg cells respond less to insulin and glucose challenge and show a reduction in insulin signaling. When subjecting animals with Hpgd-deficient Treg cells to a high fat diet (HFD), we could not detect a difference in weight gain when compared to wildtype littermate control animals. Even though we could detect a slight decrease in insulin responsiveness in animals on a HFD with Hpgd-deficient Treg cells, no difference in the VAT-resident immune cell population or in any other metabolic parameters could be observed. Additionally, in peripheral blood from human type II diabetes (T2D) patients we observed a dysregulation of the Treg cell population as well as a decrease in HPGD expression in these cells compared to healthy, age-matched controls. Taken together, these data indicate that both in humans and in the murine system, HPGD expression in Treg cells might be involved in metabolic regulation. Finally, we analyzed the role of the Treg cell specific transcription factor mesenchyme homeobox 1 (MEOX1) for HPGD expression. We found that MEOX1 is highly upregulated in human Treg cells, especially after stimulation with interleukin (IL) 2. Furthermore, we could show that while MEOX1 expression, like HPGD, is regulated by FOXP3, a loss of MEOX1 does not affect HPGD expression, thus disproving our hypothesis that HPGD may be regulated by the transcription factor MEOX1. Taken together, we could describe that HPGD is an important mediator of Treg cell suppression, independently of MEOX1. We found that a Treg cell specific deletion of Hpgd in the mouse leads to a dysregulation of the metabolism, and that HPGD levels are significantly decreased in Treg cells isolated from the peripheral blood of T2D patients compared to Treg cells isolated from healthy subjects
