Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction

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.