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

Lisa Schmidleithner, Yasser Thabet, Eva Schönfeld, Maren Köhne, Daniel Sommer, Zeinab Abdullah, Timothy Sadlon, Collins Osei-Sarpong, Kotha Subbaramaiah, Francesca Copperi, Kristian Haendler, Tamas Varga, Oliver Schanz, Svenja Bourry, Kevin Bassler, Wolfgang Krebs, Annika E. Peters, Ann Kathrin Baumgart, Maria Schneeweiss, Kathrin KleeSusanne V. Schmidt, Simone Nüssing, Jil Sander, Naganari Ohkura, Andreas Waha, Tim Sparwasser, F. Thomas Wunderlich, Irmgard Förster, Thomas Ulas, Heike Weighardt, Shimon Sakaguchi, Alexander Pfeifer, Matthias Blüher, Andrew J. Dannenberg, Nerea Ferreirós, Louis J. Muglia, Claudia Wickenhauser, Simon C. Barry, Joachim L. Schultze, Marc Beyer

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1232-1248.e14
JournalImmunity
Volume50
Issue number5
DOIs
StatePublished - May 21 2019

Keywords

  • Foxp3
  • HPGD
  • PGE
  • adipose tissue
  • regulatory T cells
  • suppressive function
  • type 2 diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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