TY - JOUR
T1 - Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction
AU - Schmidleithner, Lisa
AU - Thabet, Yasser
AU - Schönfeld, Eva
AU - Köhne, Maren
AU - Sommer, Daniel
AU - Abdullah, Zeinab
AU - Sadlon, Timothy
AU - Osei-Sarpong, Collins
AU - Subbaramaiah, Kotha
AU - Copperi, Francesca
AU - Haendler, Kristian
AU - Varga, Tamas
AU - Schanz, Oliver
AU - Bourry, Svenja
AU - Bassler, Kevin
AU - Krebs, Wolfgang
AU - Peters, Annika E.
AU - Baumgart, Ann Kathrin
AU - Schneeweiss, Maria
AU - Klee, Kathrin
AU - Schmidt, Susanne V.
AU - Nüssing, Simone
AU - Sander, Jil
AU - Ohkura, Naganari
AU - Waha, Andreas
AU - Sparwasser, Tim
AU - Wunderlich, F. Thomas
AU - Förster, Irmgard
AU - Ulas, Thomas
AU - Weighardt, Heike
AU - Sakaguchi, Shimon
AU - Pfeifer, Alexander
AU - Blüher, Matthias
AU - Dannenberg, Andrew J.
AU - Ferreirós, Nerea
AU - Muglia, Louis J.
AU - Wickenhauser, Claudia
AU - Barry, Simon C.
AU - Schultze, Joachim L.
AU - Beyer, Marc
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5/21
Y1 - 2019/5/21
N2 - 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.
AB - 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.
KW - Foxp3
KW - HPGD
KW - PGE
KW - adipose tissue
KW - regulatory T cells
KW - suppressive function
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85065247977&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065247977&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2019.03.014
DO - 10.1016/j.immuni.2019.03.014
M3 - Article
C2 - 31027998
AN - SCOPUS:85065247977
SN - 1074-7613
VL - 50
SP - 1232-1248.e14
JO - Immunity
JF - Immunity
IS - 5
ER -