title: De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells.
abstract: Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Luciana
authors.identifier: 0000000296773483
authors.initials: L
authors.lastname: Berod
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Friedrich
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Amrita
authors.initials: A
authors.lastname: Nandan
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Jenny
authors.identifier: 0000000323424634
authors.initials: J
authors.lastname: Freitag
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hagemann
authors.affiliation: Helmholtz Institute for Pharmaceutical Research, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harmrolfs
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Sandouk
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hesse
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Carla N
authors.initials: CN
authors.lastname: Castro
authors.affiliation: 1] Institute of Pharmacology, Hannover Medical School, Hannover, Germany. [2] Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bähre
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tschirner
authors.affiliation: Institute of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Gorinski
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gohmert
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Mayer
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.affiliation: Institute of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
authors.forename: Evgeni
authors.initials: E
authors.lastname: Ponimaskin
authors.affiliation: Department of Chemical Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Wolf-Rainer
authors.initials: WR
authors.lastname: Abraham
authors.affiliation: Helmholtz Institute for Pharmaceutical Research, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lochner
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007114:Immunization; D050155:Lipogenesis / Q000187:drug effects; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology
chemical_list: D005227:Fatty Acids; D018942:Macrolides; C086151:soraphen A; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase