Journal Article

DZNE-2020-07031

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction.

Schmidleithner, L. (First author)DZNE* ; Thabet, Y. ; Schönfeld, E. ; Köhne, M.DZNE* ; Sommer, D. ; Abdullah, Z. ; Sadlon, T. ; Osei-Sarpong, C.DZNE* ; Subbaramaiah, K. ; Copperi, F. ; Haendler, K. ; Varga, T.DZNE* ; Schanz, O. ; Bourry, S.DZNE* ; Bassler, K. ; Krebs, W. ; Peters, A. E. ; Baumgart, A.-K. ; Schneeweiss, M. ; Klee, K. ; Schmidt, S. V. ; Nüssing, S. ; Sander, J. ; Ohkura, N. ; Waha, A. ; Sparwasser, T. ; Wunderlich, F. T. ; Förster, I. ; Ulas, T.Extern* ; Weighardt, H. ; Sakaguchi, S. ; Pfeifer, A. ; Blüher, M. ; Dannenberg, A. J. ; Ferreirós, N. ; Muglia, L. J. ; Wickenhauser, C. ; Barry, S. C. ; Schultze, J. L.DZNE* ; Beyer, M. (Last author)DZNE*

2019
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.immuni.2019.03.014

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.

Keyword(s): 3T3 Cells (MeSH) ; Animals (MeSH) ; Cell Line (MeSH) ; Diabetes Mellitus, Type 2: metabolism (MeSH) ; Dinoprostone: analogs & derivatives (MeSH) ; Dinoprostone: metabolism (MeSH) ; HEK293 Cells (MeSH) ; Homeostasis: immunology (MeSH) ; Humans (MeSH) ; Hydroxyprostaglandin Dehydrogenases: genetics (MeSH) ; Hydroxyprostaglandin Dehydrogenases: metabolism (MeSH) ; Insulin Resistance: genetics (MeSH) ; Intra-Abdominal Fat: cytology (MeSH) ; Intra-Abdominal Fat: immunology (MeSH) ; Jurkat Cells (MeSH) ; Lymphocyte Activation: immunology (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; STAT5 Transcription Factor: metabolism (MeSH) ; T-Lymphocytes, Regulatory: enzymology (MeSH) ; T-Lymphocytes, Regulatory: immunology (MeSH) ; STAT5 Transcription Factor ; 15-ketoprostaglandin E2 ; Hydroxyprostaglandin Dehydrogenases ; Dinoprostone

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Contributing Institute(s):

1. Immunogenomics and Neurodegeneration (AG Beyer)
2. Cryo-electron microscopy and tomography (AG Alamoudi)
3. Platform for Single Cell Genomics and Epigenomics (Schultze - PRECISE)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 40 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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