Abstract:
Regulatory T cells (Treg cells) are important for pre-
venting autoimmunity and maintaining tissue homeo-
stasis, but whether Treg cells can adopt tissue- or
immune-context-specific suppressive mechanisms
is unclear. Here, we found that the enzyme hydroxy-
prostaglandin dehydrogenase (HPGD), which catab-
olizes 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-g (PPARg)-induced HPGD expression in
VAT Treg cells, and consequential Treg-cell-medi-
ated generation of 15-keto PGE2 suppressed conven-
tional 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 mecha-
nism used by Treg cells to maintain adipose tissue
homeostasis.
