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

ABSTRACT: 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-γ ligand 15-keto PGE2. PPAR-γ-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE123887 | GEO | 2019/10/07

REPOSITORIES: GEO

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

Project description: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-γ ligand 15-keto PGE2. PPAR-γ-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.

2019-10-07 | GSE123886 | GEO

Prostaglandin E2-mediated T cell suppression requires expression of hydroxyprostaglandin dehydrogenase in regulatory T cells.

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A PPAR?-FGF1 axis is required for adaptive adipose remodeling

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TGF-β1 licensed murine mesenchymal stromal cells show superior therapeutic efficacy in modulating corneal allograft immune rejection in vivo

Project description:We report a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with TGF-β1 (TGF-β MSC) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes (Tregs) following co-culture assays. These TGF-β MSC-expanded Tregs also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably, elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for un-licensed MSC treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (i) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent; (ii) TGF-β MSC’s enhanced immunosuppressive capacity is contact-dependent and (iii) enhanced secretion of PGE2 (via prostaglandin EP4 receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.

2020-08-31 | GSE150008 | GEO

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