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 - Funding Information:
We thank M. Schell, H. Theis, and M. Kraut for technical assistance; J. Oldenburg for blood samples from healthy individuals; B. Balderas and N. Warner for providing HPGD antibody; C. Benoist for microarray and clinical data from T2D patients; A. Rudensky for Foxp3-Cre-YFP mice; and W. Kastenmüller for critical discussions. CD1d tetramer and unloaded control tetramer were kindly provided by the NIH tetramer core facility. M. Beyer was funded by the Wilhelm-Sander-Foundation and the German Research Foundation (GRF)(SFB 832 and BE 4427/3-1). J.L.S. was funded by the GRF (SFB 832, SFB 704, INST 217/576-1, and INST 217/577-1). I.F. was funded by the GRF (SFB 704). M. Beyer, J.L.S. W.K. and I.F. are members of the excellence cluster ImmunoSensation2 (EXC2151-390873048). N.F. is supported by the LOEWE program from the state of Hesse (Translational Medicine and Pharmacology). S.C.B. is supported by NHMRC project grants 339123 and 565314. K.S. and A.J.D. received support from the Breast Cancer Research Foundation. L.S. Y.T. and E.S. performed qPCR, WB, overexpression experiments and functional analysis, murine experiments, and analyzed data; W.K. performed histone methylation studies; K.K. K.B. K.H. T.U. and J.S. performed bioinformatic analysis; M.S. and S.V.S. performed HPGD overexpression; Z.A. D.S. M.K. A.-K.B. A.E.P. C.O.-S. S.N. O.S. I.F. and H.W. performed and analyzed in vivo experiments; S.B. and T.V. performed in vitro assays; K.S. and A.J.D. analyzed HPGD activity; A.W. performed, designed, and supervised DNA methylation experiments; N.F. supervised the LC-MS/MS experiments; N.O. T.S. M. Blüher, S.S. and L.J.M. provided vital analytical tools; C.W. performed IHC; T.S. and S.C.B. designed, performed, and supervised ChIP experiments; F.C. A.P. and F.T.W. designed and performed metabolic experiments; and J.L.S. and M. Beyer supervised and analyzed experiments and wrote the manuscript. All authors discussed the results and commented on the manuscript. J.L.S. and M. Beyer have applied for several US and international patents on Treg cell biology.
Funding Information:
We thank M. Schell, H. Theis, and M. Kraut for technical assistance; J. Oldenburg for blood samples from healthy individuals; B. Balderas and N. Warner for providing HPGD antibody; C. Benoist for microarray and clinical data from T2D patients; A. Rudensky for Foxp3-Cre-YFP mice; and W. Kastenmüller for critical discussions. CD1d tetramer and unloaded control tetramer were kindly provided by the NIH tetramer core facility. M. Beyer was funded by the Wilhelm-Sander-Foundation and the German Research Foundation (GRF) ( SFB 832 and BE 4427/3-1 ). J.L.S. was funded by the GRF ( SFB 832 , SFB 704 , INST 217/576-1 , and INST 217/577-1 ). I.F. was funded by the GRF ( SFB 704 ). M. Beyer, J.L.S., W.K., and I.F. are members of the excellence cluster ImmunoSensation2 ( EXC2151-390873048 ). N.F. is supported by the LOEWE program from the state of Hesse (Translational Medicine and Pharmacology). S.C.B. is supported by NHMRC project grants 339123 and 565314 . K.S. and A.J.D. received support from the Breast Cancer Research Foundation .
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
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U2 - 10.1016/j.immuni.2019.03.014
DO - 10.1016/j.immuni.2019.03.014
M3 - Article
C2 - 31027998
AN - SCOPUS:85065247977
VL - 50
SP - 1232-1248.e14
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 5
ER -