Abstract
Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.
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•HPGD is specifically upregulated in Treg cells and confers suppressive capabilities•HPGD-induced Tconv cell suppression is in part mediated by PPARγ signaling•HPGD expression in Treg cells is vital for VAT homeostasis and metabolic regulation•T2D patients have a reduced Treg cell fraction expressing lower amounts of HPGD
Regulatory T (Treg) cells are important for preventing autoimmunity and maintaining tissue homeostasis. Schmidleithner et al. report a hydroxyprostaglandin dehydrogenase (HPGD)-mediated tissue- and context-dependent suppressor mechanism used by Treg cells to maintain adipose tissue homeostasis through the metabolism of PGE2 into the PPARγ ligand 15-keto-PGE2, which is conserved in human and mouse.