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 Klee; Susanne 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

doi:10.1016/j.immuni.2019.03.014

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

70 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 language	English (US)
Pages (from-to)	1232-1248.e14
Journal	Immunity
Volume	50
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2019.03.014
State	Published - 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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10.1016/j.immuni.2019.03.014

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Schmidleithner, L., Thabet, Y., Schönfeld, E., Köhne, M., Sommer, D., Abdullah, Z., Sadlon, T., Osei-Sarpong, C., Subbaramaiah, K., Copperi, F., Haendler, K., Varga, T., Schanz, O., Bourry, S., Bassler, K., Krebs, W., Peters, A. E., Baumgart, A. K., Schneeweiss, M., ... Beyer, M. (2019). Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction. Immunity, 50(5), 1232-1248.e14. https://doi.org/10.1016/j.immuni.2019.03.014

Schmidleithner, L, Thabet, Y, Schönfeld, E, Köhne, M, Sommer, D, Abdullah, Z, Sadlon, T, Osei-Sarpong, C, Subbaramaiah, K, Copperi, F, Haendler, K, Varga, T, Schanz, O, Bourry, S, Bassler, K, Krebs, W, Peters, AE, Baumgart, AK, Schneeweiss, M, Klee, K, Schmidt, SV, Nüssing, S, Sander, J, Ohkura, N, Waha, A, Sparwasser, T, Wunderlich, FT, Förster, I, Ulas, T, Weighardt, H, Sakaguchi, S, Pfeifer, A, Blüher, M, Dannenberg, AJ, Ferreirós, N, Muglia, LJ, Wickenhauser, C, Barry, SC, Schultze, JL & Beyer, M 2019, 'Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction', Immunity, vol. 50, no. 5, pp. 1232-1248.e14. https://doi.org/10.1016/j.immuni.2019.03.014

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title = "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 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, adipose tissue, regulatory T cells, suppressive function, type 2 diabetes",

author = "Lisa Schmidleithner and Yasser Thabet and Eva Sch{\"o}nfeld and Maren K{\"o}hne and Daniel Sommer and Zeinab Abdullah and Timothy Sadlon and Collins Osei-Sarpong and Kotha Subbaramaiah and Francesca Copperi and Kristian Haendler and Tamas Varga and Oliver Schanz and Svenja Bourry and Kevin Bassler and Wolfgang Krebs and Peters, {Annika E.} and Baumgart, {Ann Kathrin} and Maria Schneeweiss and Kathrin Klee and Schmidt, {Susanne V.} and Simone N{\"u}ssing and Jil Sander and Naganari Ohkura and Andreas Waha and Tim Sparwasser and Wunderlich, {F. Thomas} and Irmgard F{\"o}rster and Thomas Ulas and Heike Weighardt and Shimon Sakaguchi and Alexander Pfeifer and Matthias Bl{\"u}her and Dannenberg, {Andrew J.} and Nerea Ferreir{\'o}s and Muglia, {Louis J.} and Claudia Wickenhauser and Barry, {Simon C.} and Schultze, {Joachim L.} and Marc Beyer",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = may,

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doi = "10.1016/j.immuni.2019.03.014",

language = "English (US)",

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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

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

Abstract

Keywords

ASJC Scopus subject areas

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