De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells

Nat Med. 2014 Nov;20(11):1327-33. doi: 10.1038/nm.3704. Epub 2014 Oct 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Cell Differentiation / drug effects
  • Cell Lineage* / drug effects
  • Cell Proliferation / drug effects
  • Fatty Acids / biosynthesis*
  • Glycolysis / drug effects
  • Humans
  • Immunization
  • Lipogenesis / drug effects
  • Macrolides / chemistry
  • Macrolides / pharmacology
  • Metabolic Networks and Pathways / drug effects
  • Metabolome / drug effects
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / cytology*
  • Th17 Cells / drug effects
  • Th17 Cells / immunology


  • Fatty Acids
  • Macrolides
  • soraphen A
  • ACACA protein, human
  • Acetyl-CoA Carboxylase