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

Immunity. 2019 May 21;50(5):1232-1248.e14. doi: 10.1016/j.immuni.2019.03.014. Epub 2019 Apr 23.


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.

Keywords: Foxp3; HPGD; PGE(2); adipose tissue; regulatory T cells; suppressive function; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / metabolism
  • Dinoprostone / analogs & derivatives*
  • Dinoprostone / metabolism*
  • HEK293 Cells
  • Homeostasis / immunology
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism*
  • Insulin Resistance / genetics
  • Intra-Abdominal Fat / cytology
  • Intra-Abdominal Fat / immunology*
  • Jurkat Cells
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Knockout
  • STAT5 Transcription Factor / metabolism
  • T-Lymphocytes, Regulatory / enzymology*
  • T-Lymphocytes, Regulatory / immunology*


  • STAT5 Transcription Factor
  • 15-ketoprostaglandin E2
  • Hydroxyprostaglandin Dehydrogenases
  • Dinoprostone