1. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
- Author
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Berod, Luciana, Friedrich, Christin, Nandan, Amrita, Freitag, Jenny, Hagemann, Stefanie, Harmrolfs, Kirsten, Sandouk, Aline, Hesse, Christina, Castro, Carla N., Bahre, Heike, Tschirner, Sarah K., Gorinski, Nataliya, Gohmert, Melanie, Mayer, Christian T., Huehn, Jochen, Ponimaskin, Evgeni, Abraham, Wolf-Rainer, Muller, Rolf, Lochner, Matthias, and Sparwasser, Tim
- Subjects
T cells -- Health aspects -- Research -- Analysis ,Fatty acids -- Synthesis ,Biological sciences ,Health - Abstract
Interleukin-17 (IL-17)-secreting T cells of the T helper 17 ([T.sub.H]17) 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 [T.sub.H]17 cells and promotes the development of anti-inflammatory Foxp[3.sup.+] regulatory T ([T.sub.reg]) cells. We show that [T.sub.H]17 cells, but not [T.sub.reg] cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although [T.sub.H]17 cells use this pathway to produce phospholipids for cellular membranes, [T.sub.reg] 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 [T.sub.H]17 cell-mediated autoimmune disease. Our results indicate fundamental differences between [T.sub.H]17 cells and [T.sub.reg] 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 [T.sub.H]17 cell-mediated inflammatory diseases., To develop from naive cells into distinct T cell lineages, activated T cells undergo a massive metabolic switch to cope with the demands of cell growth and multiple rounds of [...]
- Published
- 2014