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De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
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Journal Article
De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
2014
Overview
T
H
17 and T
reg
cell development are reciprocally regulated by
de novo
fatty acid synthesis, and inhibition of acetyl-CoA carboxylase 1 (ACC1) attenuates T
H
17 cell–mediated autoimmune disease.
Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (T
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
H
17 cells and promotes the development of anti-inflammatory Foxp3
+
regulatory T (T
reg
) cells. We show that T
H
17 cells, but not T
reg
cells, depend on ACC1-mediated
de novo
fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although T
H
17 cells use this pathway to produce phospholipids for cellular membranes, T
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
H
17 cell–mediated autoimmune disease. Our results indicate fundamental differences between T
H
17 cells and T
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
H
17 cell–mediated inflammatory diseases.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Acetyl-CoA Carboxylase - antagonists & inhibitors
/ Acetyl-CoA Carboxylase - metabolism
/ Analysis
/ Animals
/ Cell Differentiation - drug effects
/ Cell Proliferation - drug effects
/ Humans
/ letter
/ Metabolic Networks and Pathways - drug effects
/ T cells
/ T-Lymphocytes, Regulatory - cytology
/ T-Lymphocytes, Regulatory - drug effects
